Quinazoles useful as modulators of ion channels

ABSTRACT

The present invention relates to compounds useful as inhibitors of voltage-gated sodium channels and calcium channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

PRIORITY INFORMATION

The present application claims priority under 35 U.S.C. §119 to U.S.Provisional Application Nos. 60/451,458 filed Mar. 3, 2003, entitled“Compositions Useful as Inhibitors of Voltage-Gated Sodium Channels”,and 60/463,797, filed Apr. 18, 2003, entitled “Compositions Useful asInhibitors of Voltage-Gated Sodium Channels”, and the entire contents ofeach of these applications is hereby incorporated by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors of ionchannels. The invention also provides pharmaceutically acceptablecompositions comprising the compounds of the invention and methods ofusing the compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

Na channels are central to the generation of action potentials in allexcitable cells such as neurons and myocytes. They play key roles inexcitable tissue including brain, smooth muscles of the gastrointestinaltract, skeletal muscle, the peripheral nervous system, spinal cord andairway. As such they play key roles in a variety of disease states suchas epilepsy (See, Moulard, B. and D. Bertrand (2002) “Epilepsy andsodium channel blockers” Expert Opin. Ther. Patents 12(1): 85-91)), pain(See, Waxman, S. G., S. Dib-Hajj, et al. (1999) “Sodium channels andpain” Proc Natl Acad Sci USA 96(14): 7635-9 and Waxman, S. G., T. R.Cummins, et al. (2000) “Voltage-gated sodium channels and the molecularpathogenesis of pain: a review” J Rehabil Res Dev 37(5): 517-28),myotonia (See, Meola, G. and V. Sansone (2000) “Therapy in myotonicdisorders and in muscle channelopathies” Neurol Sci 21(5): S953-61 andMankodi, A. and C. A. Thornton (2002) “Myotonic syndromes” Curr OpinNeurol 15(5): 545-52), ataxia (See, Meisler, M. H., J. A. Kearney, etal. (2002) “Mutations of voltage-gated sodium channels in movementdisorders and epilepsy” Novartis Found Symp 241: 72-81), multiplesclerosis (See, Black, J. A., S. Dib-Hajj, et al. (2000) “Sensoryneuron-specific sodium channel SNS is abnormally expressed in the brainsof mice with experimental allergic encephalomyelitis and humans withmultiple sclerosis” Proc Natl Acad Sci USA 97(21): 11598-602, andRenganathan, M., M. Gelderblom, et al. (2003) “Expression of Na(v)1.8sodium channels perturbs the firing patterns of cerebellar purkinjecells” Brain Res 959(2): 235-42), irritable bowel (See, Su, X., R. E.Wachtel, et al. (1999) “Capsaicin sensitivity and voltage-gated sodiumcurrents in colon sensory neurons from rat dorsal root ganglia” Am JPhysiol 277(6 Pt 1): G1180-8, and Laird, J. M., V. Souslova, et al.(2002) “Deficits in visceral pain and referred hyperalgesia in Nav1.8(SNS/PN3)-null mice” J Neurosci 22(19): 8352-6), urinary incontinenceand visceral pain (See, Yoshimura, N., S. Seki, et al. (2001) “Theinvolvement of the tetrodotoxin-resistant sodium channel Na(v)1.8(PN3/SNS) in a rat model of visceral pain” J Neurosci 21(21): 8690-6),as well as an array of psychiatry dysfunctions such as anxiety anddepression (See, Hurley, S. C. (2002) “Lamotrigine update and its use inmood disorders” Ann Pharmacother 36(5): 860-73).

Voltage gated Na channels comprise a gene family consisting of 9different subtypes (NaV1.1-NaV1.9). As shown in Table 1, these subtypesshow tissue specific localization and functional differences (See,Goldin, A. L. (2001) “Resurgence of sodium channel research” Annu RevPhysiol 63: 871-94). Three members of the gene family (NaV1.8, 1.9, 1.5)are resistant to block by the well-known Na channel blocker TTX,demonstrating subtype specificity within this gene family. Mutationalanalysis has identified glutamate 387 as a critical residue for TTXbinding (See, Noda, M., H. Suzuki, et al. (1989) “A single pointmutation confers tetrodotoxin and saxitoxin insensitivity on the sodiumchannel II” FEBS Lett 259(1): 213-6).

TABLE 1 (Abbreviations: CNS = central nervous system, PNS = peripheralnervous sytem, DRG = dorsal root ganglion, TG = Trigeminal ganglion): Naisoform Tissue TTX IC50 Indications NaV1.1 CNS, PNS 10 nM Pain,Epilepsy, soma of neurodegeneration neurons NaV1.2 CNS, high in 10 nMNeurodegeneration axons Epilepsy NaV1.3 CNS, 15 nM Pain embryonic,injured nerves NaV1.4 Skeletal 25 nM Myotonia muscle NaV1.5 Heart 2 μMArrythmia, long QT NaV1.6 CNS 6 nM Pain, movement disorders widespread,most abuntant NaV1.7 PNS, DRG, 25 nM Pain, Neuroendocrine terminalsdisorders neuroendocrine NaV1.8 PNS, small >50 μM Pain neurons in DRG &TG NaV1.9 PNS, small 1 μM Pain neurons in DRG & TG

In general, voltage-gated sodium channels (NaVs) are responsible forinitiating the rapid upstroke of action potentials in excitable tissuein nervous system, which transmit the electrical signals that composeand encode normal and aberrant pain sensations. Antagonists of NaVchannels can attenuate these pain signals and are useful for treating avariety of pain conditions, including but not limited to acute, chronic,inflammatory, and neuropathic pain. Known NaV antagonists, such as TTX,lidocaine (See Mao, J. and L. L. Chen (2000) “Systemic lidocaine forneuropathic pain relief” Pain 87(1): 7-17.) bupivacaine, phenyloin (See,Jensen, T. S. (2002) “Anticonvulsants in neuropathic pain: rationale andclinical evidence” Eur J Pain 6 (Suppl A): 61-8), lamotrigine (See,Rozen, T. D. (2001) “Antiepileptic drugs in the management of clusterheadache and trigeminal neuralgia” Headache 41 Suppl 1: S25-32 andJensen, T. S. (2002) “Anticonvulsants in neuropathic pain: rationale andclinical evidence” Eur J Pain 6 (Suppl A): 61-8.), and carbamazepine(See, Backonja, M. M. (2002) “Use of anticonvulsants for treatment ofneuropathic pain” Neurology 59(5 Suppl 2): S14-7), have been shown to beuseful attenuating pain in humans and animal models.

Hyperalgesia (extreme sensitivity to something painful) that develops inthe presence of tissue injury or inflammation reflects, at least inpart, an increase in the excitability of high-threshold primary afferentneurons innervating the site of injury. Voltage sensitive sodiumchannels activation is critical for the generation and propagation ofneuronal action potentials. There is a growing body of evidenceindicating that modulation of NaV currents is an endogenous mechanismused to control neuronal excitability (See, Goldin, A. L. (2001)“Resurgence of sodium channel research” Annu Rev Physiol 63: 871-94.).Several kinetically and pharmacologically distinct voltage-gated sodiumchannels are found in dorsal root ganglion (DRG) neurons. TheTTX-resistant current is insensitive to micromolar concentrations oftetrodotoxin, and displays slow activation and inactivation kinetics anda more depolarized activation threshold when compared to othervoltage-gated sodium channels. TTX-resistant sodium currents areprimarily restricted to a subpopulation of sensory neurons likely to beinvolved in nociception. Specifically, TTX-resistant sodium currents areexpressed almost exclusively in neurons that have a small cell-bodydiameter; and give rise to small-diameter slow-conducting axons and thatare responsive to capsaicin. A large body of experimental evidencedemonstrates that TTX-resistant sodium channels are expressed onC-fibers and are important in the transmission of nociceptiveinformation to the spinal cord.

Intrathecal administration of antisense oligo-deoxynucleotides targetinga unique region of the TTX-resistant sodium channel (NaV1.8) resulted ina significant reduction in PGE₂-induced hyperalgesia (See, Khasar, S.G., M. S. Gold, et al. (1998) “A tetrodotoxin-resistant sodium currentmediates inflammatory pain in the rat” Neurosci Lett 256(1): 17-20).More recently, a knockout mouse line was generated by Wood andcolleagues, which lacks functional NaV1.8. The mutation has an analgesiceffect in tests assessing the animal's response to the inflammatoryagent carrageenan (See, Akopian, A. N., V. Souslova, et al. (1999) “Thetetrodotoxin-resistant sodium channel SNS has a specialized function inpain pathways” Nat Neurosci 2(6): 541-8.). In addition, deficit in bothmechano- and thermoreception were observed in these animals. Theanalgesia shown by the Nav1.8 knockout mutants is consistent withobservations about the role of TTX-resistant currents in nociception.

Immunohistochemical, in-situ hybridization and in-vitroelectrophysiology experiments have all shown that the sodium channelNaV1.8 is selectively localized to the small sensory neurons of thedorsal root ganglion and trigeminal ganglion (See, Akopian, A. N., L.Sivilotti, et al. (1996) “A tetrodotoxin-resistant voltage-gated sodiumchannel expressed by sensory neurons” Nature 379(6562): 257-62.). Theprimary role of these neurons is the detection and transmission ofnociceptive stimuli. Antisense and immunohistochemical evidence alsosupports a role for NaV1.8 in neuropathic pain (See, Lai, J., M. S.Gold, et al. (2002) “Inhibition of neuropathic pain by decreasedexpression of the tetrodotoxin-resistant sodium channel, NaV1.8” Pain95(1-2): 143-52, and Lai, J., J. C. Hunter, et al. (2000) “Blockade ofneuropathic pain by antisense targeting of tetrodotoxin-resistant sodiumchannels in sensory neurons” Methods Enzymol 314: 201-13.). NaV1.8protein is upregulated along uninjured C-fibers adjacent to the nerveinjury. Antisense treatment prevents the redistribution of NaV1.8 alongthe nerve and reverses neuropathic pain. Taken together thegene-knockout and antisense data support a role for NaV1.8 in thedetection and transmission of inflammatory and neuropathic pain.

In neuropathic pain states there is a remodeling of Na channeldistribution and subtype. In the injured nerve, expression of NaV1.8 andNaV1.9 are greatly reduced whereas expression of the TTX sensitivesubunit NaV1.3 is 5-10 fold upregulated (See, Dib-Hajj, S. D., J. Fjell,et al. (1999) “Plasticity of sodium channel expression in DRG neurons inthe chronic constriction injury model of neuropathic pain.” Pain 83(3):591-600.) The timecourse of the increase in NaV1.3 parallels theappearance of allodynia in animal models subsequent to nerve injury. Thebiophysics of the NaV1.3 channel is distinctive in that it shows veryfast repriming after inactivation following an action potential. Thisallows for sustained rates of high firing as is often seen in theinjured nerve (See, Cummins, T. R., F. Aglieco, et al. (2001) “Nav1.3sodium channels: rapid repriming and slow closed-state inactivationdisplay quantitative differences after expression in a mammalian cellline and in spinal sensory neurons” J Neurosci 21(16): 5952-1.). NaV1.3is expressed in the central and peripheral systems of man. NaV1.9 issimilar to NaV1.8 as it is selectively localized to small sensoryneurons of the dorsal root ganglion and trigeminal ganglion (See, Fang,X., L. Djouhri, et al. (2002). “The presence and role of thetetrodotoxin-resistant sodium channel Na(v)1.9 (NaN) in nociceptiveprimary afferent neurons.” J Neurosci 22(17): 7425-33.). It has a slowrate of inactivation and left-shifted voltage dependence for activation(See, Dib-Hajj, S., J. A. Black, et al. (2002) “NaN/Nav1.9: a sodiumchannel with unique properties” Trends Neurosci 25(5): 253-9.). Thesetwo biophysical properties allow NaV1.9 to play a role in establishingthe resting membrane potential of nociceptive neurons. The restingmembrane potential of NaV1.9 expressing cells is in the −55 to −50 mVrange compared to −65 mV for most other peripheral and central neurons.This persistent depolarization is in large part due to the sustainedlow-level activation of NaV1.9 channels. This depolarization allows theneurons to more easily reach the threshold for firing action potentialsin response to nociceptive stimuli. Compounds that block the NaV1.9channel may play an important role in establishing the set point fordetection of painful stimuli. In chronic pain states, nerve and nerveending can become swollen and hypersensitive exhibiting high frequencyaction potential firing with mild or even no stimulation. Thesepathologic nerve swellings are termed neuromas and the primary Nachannels expressed in them are NaV1.8 and NaV1.7 (See, Kretschmer, T.,L. T. Happel, et al. (2002) “Accumulation of PN1 and PN3 sodium channelsin painful human neuroma-evidence from immunocytochemistry” ActaNeurochir (Wien) 144(8): 803-10; discussion 810.). NaV1.6 and NaV1.7 arealso expressed in dorsal root ganglion neurons and contribute to thesmall TTX sensitive component seen in these cells. NaV1.7 in particularmy therefore be a potential pain target in addition to it's role inneuroendocrine excitability (See, Klugbauer, N., L. Lacinova, et al.(1995) “Structure and functional expression of a new member of thetetrodotoxin-sensitive voltage-activated sodium channel family fromhuman neuroendocrine cells” Embo J 14(6): 1084-90).

NaV1.1 (See, Sugawara, T., E. Mazaki-Miyazaki, et al. (2001) “Nav1.1mutations cause febrile seizures associated with afebrile partialseizures.” Neurology 57(4): 703-5.) and NaV1.2 (See, Sugawara, T., Y.Tsurubuchi, et al. (2001) “A missense mutation of the Na+ channel alphaII subunit gene Na(v)1.2 in a patient with febrile and afebrile seizurescauses channel dysfunction” Proc Natl Acad Sci USA 98(11): 6384-9) havebeen linked to epilepsy conditions including febrile seizures. There areover 9 genetic mutations in NaV 1.1 associated with febrile seizures(See, Meisler, M. H., J. A. Kearney, et al. (2002) “Mutations ofvoltage-gated sodium channels in movement disorders and epilepsy”Novartis Found Symp 241: 72-81)

Antagonists for NaV1.5 have been developed and used to treat cardiacarrhythmias. A gene defect in NaV1.5 that produces a largernoninactivating component to the current has been linked to long QT inman and the orally available local anesthetic mexilitine has been usedto treat this condition (See, Wang, D. W., K. Yazawa, et al. (1997)“Pharmacological targeting of long QT mutant sodium channels.” J ClinInvest 99(7): 1714-20).

Several Na channel blockers are currently used or being tested in theclinic to treat epilepsy (See, Moulard, B. and D. Bertrand (2002)“Epilepsy and sodium channel blockers” Expert Opin. Ther. Patents 12(1):85-91.); acute (See, Wiffen, P., S. Collins, et al. (2000)“Anticonvulsant drugs for acute and chronic pain” Cochrane Database SystRev 3), chronic (See, Wiffen, P., S. Collins, et al. (2000)“Anticonvulsant drugs for acute and chronic pain” Cochrane Database SystRev 3, and Guay, D. R. (2001) “Adjunctive agents in the management ofchronic pain” Pharmacotherapy 21(9): 1070-81), inflammatory (See, Gold,M. S. (1999) “Tetrodotoxin-resistant Na+ currents and inflammatoryhyperalgesia.” Proc Natl Acad Sci USA 96(14): 7645-9), and neuropathicpain (See, Strichartz, G. R., Z. Zhou, et al. (2002) “Therapeuticconcentrations of local anaesthetics unveil the potential role of sodiumchannels in neuropathic pain” Novartis Found Symp 241: 189-201, andSandner-Kiesling, A., G. Rumpold Seitlinger, et al. (2002) “Lamotriginemonotherapy for control of neuralgia after nerve section” ActaAnaesthesiol Scand 46(10): 1261-4); cardiac arrhythmias (See An, R. H.,R. Bangalore, et al. (1996) “Lidocaine block of LQT-3 mutant human Na+channels” Circ Res 79(1): 103-8, and Wang, D. W., K. Yazawa, et al.(1997) “Pharmacological targeting of long QT mutant sodium channels” JClin Invest 99(7): 1714-20); neuroprotection (See, Taylor, C. P. and L.S. Narasimhan (1997) “Sodium channels and therapy of central nervoussystem diseases” Adv Pharmacol 39: 47-98) and as anesthetics (See,Strichartz, G. R., Z. Zhou, et al. (2002) “Therapeutic concentrations oflocal anaesthetics unveil the potential role of sodium channels inneuropathic pain.” Novartis Found Symp 241: 189-201)

Calcium channels are membrane-spanning, multi-subunit proteins thatallow Ca entry from the external milieu and concurrent depolarization ofthe cell's membrane potential. Traditionally calcium channels have beenclassified based on their functional characteristics such as low voltageor high voltage activated and their kinetics (L, T, N, P, Q). Theability to clone and express the calcium channel subunits has lead to anincreased understanding of the channel composition that produces thesefunctional responses. There are three primary subunit types that make upcalcium channels—α1, α2δ, and β. The α1 is the subunit containing thechannel pore and voltage sensor, α2 is primarily extracellular and isdisulfide linked to the transmembrane δ subunit, β is nonglycosylatedsubunit found bound to the cytoplasmic region of the aα1 subunit of theCa channel. Currently the various calcium channel subtypes are believedto made up of the following specific subunits:

L-type, comprising subunits α_(1C)α_(1D)α_(1F), or α_(1S), α2δ andβ_(3a)

N-Type, comprising subunits α_(1B), α2δ, β_(1b)

P-Type, comprising subunits α_(1A), α2δ, β_(4a)

Q-Type, comprising subunits α_(1A) (splice variant) α2δ, β_(4a)

R-Type, comprising subunits α_(1E), α2δ, β_(1b)

T-Type, comprising subunits α_(1G), α_(1H), or α_(1I)

Calcium channels play a central role in neurotransmitter release. Cainflux into the presynaptic terminal of a nerve process binds to andproduces a cascade of protein-protein interactions (syntaxin 1A, SNAP-25and synaptotagmin) that ultimately ends with the fusion of a synapticvesical and release of the neurotransmitter packet. Blockade of thepresynaptic calcium channels reduces the influx of Ca and produces acubic X³ decrease in neurotransmitter release.

The N type Ca channel (CaV2.2) is highly expressed at the presynapticnerve terminals of the dorsal root ganglion as it forms a synapse withthe dorsal horn neurons in lamina I and II. These neurons in turn havelarge numbers of N type Ca channels at their presynaptic terminals asthey synapse onto second and third order neurons. This pathway is veryimportant in relaying pain information to the brain.

Pain can be roughly divided into three different types: acute,inflammatory, and neuropathic. Acute pain serves an important protectivefunction in keeping the organism safe from stimuli that may producetissue damage. Severe thermal, mechanical, or chemical inputs have thepotential to cause severe damage to the organism if unheeded. Acute painserves to quickly remove the individual from the damaging environment.Acute pain by its very nature generally is short lasting and intense.Inflammatory pain on the other had may last for much longer periods oftime and it's intensity is more graded. Inflammation may occur for manyreasons including tissue damage, autoimmune response, and pathogeninvasion. Inflammatory pain is mediated by an “inflammatory soup” thatconsists of substance P, histamines, acid, prostaglandin, bradykinin,CGRP, cytokines, ATP, and neurotransmitter release. The third class ofpain is neuropathic and involves nerve damage that results inreorganization of neuronal proteins and circuits yielding a pathologic“sensitized” state that can produce chronic pain lasting for years. Thistype of pain provides no adaptive benefit and is particularly difficultto treat with existing therapies.

Pain, particularly neuropathic and intractable pain is a large unmetmedical need. Millions of individuals suffer from severe pain that isnot well controlled by current therapeutics. The current drugs used totreat pain include NSAIDS, COX2 inhibitors, opioids, tricyclicantidepressants, and anticonvulsants. Neuropathic pain has beenparticularly difficult to treat as it does not respond well to opiodsuntil high doses are reached. Gabapentin is currently the favoredtherapeutic for the treatment of neuropathic pain although it works inonly 60% of patients where it shows modest efficacy. The drug is howeververy safe and side effects are generally tolerable although sedation isan issue at higher doses.

The N type Ca channel has been validated in man by intrathecal infusionof the toxin Ziconotide for the treatment of intractable pain, cancerpain, opioid resistant pain, and neuropathic and severe pain. The toxinhas an 85% success rate for the treatment of pain in humans with agreater potency than morphine. An orally available N type Ca channelantagonist would garner a much larger share of the pain market.Ziconotide causes mast cell degranulation and produces dose-dependentcentral side effects. These include dizziness, nystagmus, agitation, anddysmetria. There is also orthostatic hypotension in some patients athigh doses. The primary risk for this target involves the CNS sideeffects seen with Ziconotide at high dosing. These include dizziness,nystagmus, agitation, and dysmetria. There is also orthostatichypotension in some patients at high doses. It is believed that this maybe due to Ziconotide induced mast cell degranulation and/or its effectson the sympathetic ganglion that like the dorsal root ganglion alsoexpresses the N type Ca channel. Use-dependent compounds that blockpreferentially in the higher frequency range >10 Hz should be helpful inminimizing these potential side-effect issues. The firing rate in man ofthe sympathetic efferents is in the 0.3 Hz range. CNS neurons can fireat high frequencies but generally only do so in short bursts of actionpotentials. Even with the selectivity imparted by use-dependenceintrinsic selectivity against the L type calcium channel is stillnecessary as it is involved in cardiac and vascular smooth musclecontraction.

Unfortunately, as described above, the efficacy of currently used sodiumchannel blockers and calcium channel blockers for the disease statesdescribed above has been to a large extent limited by a number of sideeffects. These side effects include various CNS disturbances such asblurred vision, dizziness, nausea, and sedation as well more potentiallylife threatening cardiac arrhythmias and cardiac failure. Accordingly,there remains a need to develop additional Na channel and Ca channelantagonists, preferably those with higher potency and fewer sideeffects.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are useful asinhibitors of voltage-gated sodium channels and calcium channels. Thesecompounds have the general formula I:

or a pharmaceutically acceptable derivative thereof, wherein R¹, X, R³,x, and ring A are as defined below.

These compounds and pharmaceutically acceptable compositions are usefulfor treating or lessening the severity of a variety of diseases,disorders, or conditions, including, but not limited to, acute, chronic,neuropathic, or inflammatory pain, arthritis, migrane, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,epilepsy or epilepsy conditions, neurodegenerative disorders,psychiatric disorders such as anxiety and depression, myotonia,arrythmia, movement disorders, neuroendocrine disorders, ataxia,multiple sclerosis, irritable bowel syndrome, incontinence, visceralpain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head or neck pain, severe orintractable pain, nociceptive pain, breakthrough pain, postsurgicalpain, or cancer pain.

DETAILED DESCRIPTION OF THE INVENTION I. General Description ofCompounds of the Invention

The present invention relates to compounds of formula I useful asinhibitors of voltage-gated sodium channels and calcium channels:

or a pharmaceutically acceptable salt thereof, wherein:

X is O or NR²;

wherein R¹ and R² are each independently an optionally substituted groupselected from hydrogen, C₁₋₆aliphatic, or Cy¹, wherein Cy¹ is a5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or is a 3-12-membered saturated, or partially unsaturatedmonocyclic or bicyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein Cy¹ is bondeddirectly to the nitrogen atom or is bonded through an optionallysubstituted C₁₋₄aliphatic group, wherein one or more methylene units inthe C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or R¹ and R², taken togetherwith the nitrogen atom to which they are bound, form an optionallysubstituted 3-12-membered monocyclic or bicyclic saturated, partiallyunsaturated, or fully unsaturated ring having 0-3 additional heteroatomsindependently selected from nitrogen, sulfur, or oxygen; wherein R¹ andR², or the ring formed by R¹ and R² taken together, are each optionallyand independently substituted at one or more substitutable carbon,nitrogen, or sulfur atoms with z independent occurrences of —R⁴, whereinz is 0-5;

Ring A is a 5-7-membered monocyclic aryl ring or an 8-10-memberedbicyclic aryl ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or is a 3-12-membered monocyclic orbicyclic saturated or partially unsaturated monocyclic ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein ring A is optionally substituted with y independent occurrencesof —R⁵, wherein y is 0-5, and is additionally optionally substitutedwith q independent occurrences of R^(5a), wherein q is 0-2;

x is 0-4;

each occurrence of R³, R⁴, and R⁵ is independently Q-R^(X); wherein Q isa bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacentmethylene units of Q are optionally and independently replaced by —NR—,—S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—,—SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—,—SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of R^(X)is independently selected from —R′, ═O, ═NR′, halogen, —NO₂, —CN, —OR′,—SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′,—CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′,—NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂,—OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂;

each occurrence of R^(5a) is independently an optionally substitutedC₁-C₆aliphatic group, halogen, —OR′, —SR′, —N(R′)₂, —NR′COR′,—NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂,—SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′,—COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂,or —OPO(R′)₂; and

each occurrence of R is independently hydrogen or an optionallysubstituted C₁₋₆ aliphatic group; and each occurrence of R′ isindependently hydrogen or an optionally substituted C₁₋₆ aliphaticgroup, a 3-8-membered saturated, partially unsaturated, or fullyunsaturated monocyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an 8-12 memberedsaturated, partially unsaturated, or fully unsaturated bicyclic ringsystem having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrencesof R′, are taken together with the atom(s) to which they are bound toform an optionally substituted 3-12 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments for compounds described directly above:

i) when x is 1 and R³ is optionally substituted 6-phenyl or 6-pyridyl,and R¹ is hydrogen, then R² is not Cy¹; and

ii)piperazine,1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4(2-furanylcarbonyl)-monohydrochlorideandpiperazine,1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(2,3-dihydro-1,4-benzodioxin-2-yl)carbonyl]-are excluded.

2. Compounds and Definitions:

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable”, as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-20 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-10aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-6 aliphatic carbon atoms, and in yet other embodimentsaliphatic groups contain 1-4 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₈ hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon that iscompletely saturated or that contains one or more units of unsaturation,but which is not aromatic, that has a single point of attachment to therest of the molecule wherein any individual ring in said bicyclic ringsystem has 3-7 members. Suitable aliphatic groups include, but are notlimited to, linear or branched, substituted or unsubstituted alkyl,alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “heteroaliphatic”, as used herein, means aliphatic groupswherein one or two carbon atoms are independently replaced by one ormore of oxygen, sulfur, nitrogen, phosphorus, or silicon.Heteroaliphatic groups may be substituted or unsubstituted, branched orunbranched, cyclic or acyclic, and include “heterocycle”,“heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” groups.

The term “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or“heterocyclic” as used herein means non-aromatic, monocyclic, bicyclic,or tricyclic ring systems in which one or more ring members are anindependently selected heteroatom. In some embodiments, the“heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic”group has three to fourteen ring members in which one or more ringmembers is a heteroatom independently selected from oxygen, sulfur,nitrogen, or phosphorus, and each ring in the system contains 3 to 7ring members.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” means alkyl,alkenyl or alkoxy, as the case may be, substituted with one or morehalogen atoms. The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring members, wherein at least one ring in the system is aromatic andwherein each ring in the system contains 3 to 7 ring members. The term“aryl” may be used interchangeably with the term “aryl ring”. The term“aryl” also refers to heteroaryl ring systems as defined hereinbelow.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) orheteroaryl (including heteroaralkyl and heteroarylalkoxy and the like)group may contain one or more substituents and thus may be “optionallysubstituted”. Unless otherwise defined above and herein, suitablesubstituents on the unsaturated carbon atom of an aryl or heteroarylgroup are generally selected from halogen; —R^(o); —OR^(o); —SR^(o);phenyl (Ph) optionally substituted with R^(o); —O(Ph) optionallysubstituted with R^(o); —(CH₂)₁₋₂(Ph), optionally substituted withR^(o); —CH═CH(Ph), optionally substituted with R^(o); —NO₂; —CN;—N(R^(o))₂; —NR^(o)C(O)R^(o); —NR^(o)C(S)R^(o); —NR^(o)C(O)N(R^(o))₂;—NR^(o)C(S)N(R^(o))₂; —NR^(o)CO₂R^(o); —NR^(o)NR^(o)C(O)R^(o);—NR^(o)NR^(o)C(O)N(R^(o))₂; —NR^(o)NR^(o)CO₂R^(o); —C(O)C(O)R^(o);—C(O)CH₂C(O)R^(o); —CO₂R^(o); —C(O)R^(o); —C(S)R^(o); —C(O)N(R^(o))₂;—C(S)N(R^(o))₂; —OC(O)N(R^(o))₂; —OC(O)R^(o); —C(O)N(OR^(o))R^(o);—C(NOR^(o))R^(o); —S(O)₂R^(o); —S(O)₃R^(o); —SO₂N(R^(o))₂; —S(O)R^(o);—NR^(o)SO₂N(R^(o))₂; —NR^(o)SO₂R^(o); —N(OR^(o))R^(o);—C(═NH)—N(R^(o))₂; —P(O)₂R^(o); —PO(R^(o))₂; —OPO(R^(o))₂;—(CH₂)₀₋₂NHC(O)R^(o); phenyl (Ph) optionally substituted with R^(o);—O(Ph) optionally substituted with R^(o); —(CH₂)₁₋₂(Ph), optionallysubstituted with R^(o); or —CH═CH(Ph), optionally substituted withR^(o); wherein each independent occurrence of R^(o) is selected fromhydrogen, optionally substituted C₁₋₆ aliphatic, an unsubstituted 5-6membered heteroaryl or heterocyclic ring, phenyl, —O(Ph), or —CH₂(Ph),or, notwithstanding the definition above, two independent occurrences ofR^(o), on the same substituent or different substituents, taken togetherwith the atom(s) to which each R^(o) group is bound, to form anoptionally substituted 3-12 membered saturated, partially unsaturated,or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

Optional substituents on the aliphatic group of R^(o) are selected fromNH₂, NH(C₁₋₄aliphatic), N(C₁₋₄aliphatic)₂, halogen, C₁₋₄aliphatic, OH,O(C₁₋₄aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), O(haloC₁₋₄aliphatic), or haloC₁₋₄aliphatic, wherein each of the foregoingC₁₋₄aliphatic groups of R^(o) is unsubstituted.

An aliphatic or heteroaliphatic group, or a non-aromatic heterocyclicring may contain one or more substituents and thus may be “optionallysubstituted”. Unless otherwise defined above and herein, suitablesubstituents on the saturated carbon of an aliphatic or heteroaliphaticgroup, or of a non-aromatic heterocyclic ring are selected from thoselisted above for the unsaturated carbon of an aryl or heteroaryl groupand additionally include the following: ═O, ═S, ═NNHR*, ═NN(R*)₂,═NNHC(O)R*, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), or ═NR*, where each R* isindependently selected from hydrogen or an optionally substituted C₁₋₆aliphatic group.

Unless otherwise defined above and herein, optional substituents on thenitrogen of a non-aromatic heterocyclic ring are generally selected from—R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺, —SO₂R⁺,—SO₂N(R⁺)₂, —C(═S)N(R⁺¹)₂, —C(═NH)—N(R⁺)₂, or —NR⁺SO₂R⁺; wherein R⁺ ishydrogen, an optionally substituted C₁₋₆ aliphatic, optionallysubstituted phenyl, optionally substituted —O(Ph), optionallysubstituted —CH₂(Ph), optionally substituted —(CH₂)₁₋₂(Ph); optionallysubstituted —CH═CH(Ph); or an unsubstituted 5-6 membered heteroaryl orheterocyclic ring having one to four heteroatoms independently selectedfrom oxygen, nitrogen, or sulfur, or, notwithstanding the definitionabove, two independent occurrences of R⁺, on the same substituent ordifferent substituents, taken together with the atom(s) to which each R⁺group is bound, form an optionally substituted 3-12 membered saturated,partially unsaturated, or fully unsaturated monocyclic or bicyclic ringhaving 0-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur.

Optional substituents on the aliphatic group or the phenyl ring of R⁺are selected from —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂,halogen, C₁₋₄ aliphatic, —OH, —O(C₁₋₄ aliphatic), —NO₂, —CN, —CO₂H,CO₂(C₁₋₄ aliphatic), —O(halo C₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic),wherein each of the foregoing C₁₋₄aliphatic groups of R⁺ isunsubstituted.

The term “alkylidene chain” refers to a straight or branched carbonchain that may be fully saturated or have one or more units ofunsaturation and has two points of attachment to the rest of themolecule.

As detailed above, in some embodiments, two independent occurrences ofR^(o) (or R⁺, R, R′ or any other variable similarly defined, herein),are taken together with the atom(s) to which they are bound to form anoptionally substituted 3-12 membered saturated, partially unsaturated,or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

Exemplary rings that are formed when two independent occurrences ofR^(o) (or R⁺, R, R′ or any other variable similarly defined herein), aretaken together with the atom(s) to which each variable is bound include,but are not limited to the following: a) two independent occurrences ofR^(o) (or R⁺, R, R′ or any other variable similarly defined herein) thatare bound to the same atom and are taken together with that atom to forma ring, for example, N(R^(o))₂, where both occurrences of R^(o) aretaken together with the nitrogen atom to form a piperidin-1-yl,piperazin-1-yl, or morpholin-4-yl group; and b) two independentoccurrences of R^(o) (or R⁺, R, R′ or any other variable similarlydefined herein) that are bound to different atoms and are taken togetherwith both of those atoms to form a ring, for example where a phenylgroup is substituted with two occurrences of OR^(o)

these two occurrences of R^(o) are taken together with the oxygen atomsto which they are bound to form a fused 6-membered oxygen containingring:

It will be appreciated that a variety of other rings can be formed whentwo independent occurrences of R^(o) (or R⁺, R, R′ or any other variablesimilarly defined herein) are taken together with the atom(s) to whicheach variable is bound and that the examples detailed above are notintended to be limiting.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools or probes inbiological assays.

3. Description of Exemplary Compounds:

As described generally above, for compounds of the invention, X is O orNR². Accordingly, in certain embodiments, X is NR², and compounds havethe structure of formula I-A:

In other embodiments, X is O, and compounds have the structure offormula I-B:

In certain embodiments for compounds of general formula I-A, one of R¹or R² is hydrogen, and the other of R¹ and R² is selected from anoptionally substituted C₁₋₄aliphatic group, wherein one or moremethylene units in the C₁₋₄aliphatic group are optionally replaced with—NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—, or is Cy¹,wherein Cy¹ is a 5-7-membered monocyclic aryl ring or an 8-10-memberedbicyclic aryl ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or is a 3-12-membered saturated, orpartially unsaturated monocyclic or bicyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, wherein Cy¹ isbonded directly to the nitrogen atom or is bonded through an optionallysubstituted C₁₋₄aliphatic group, wherein one or more methylene units inthe C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—.

In still other embodiments, R¹ and R² are each independently selectedfrom Cy¹, wherein Cy¹ is a 5-7-membered monocyclic aryl ring or an8-10-membered bicyclic aryl ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or is a 3-12-memberedsaturated, or partially unsaturated monocyclic or bicyclic ring having0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein Cy¹ is bonded directly to the nitrogen atom or is bonded throughan optionally substituted C₁₋₄aliphatic group, wherein one or moremethylene units in the C₁₋₄aliphatic group are optionally replaced with—NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or from anoptionally substituted C₁₋₄aliphatic group, wherein one or moremethylene units in the C₁₋₄aliphatic group are optionally replaced with—NR—, —O—, —COO—, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—.

In other embodiments, for compounds of formula I-A, one of R¹ or R² ishydrogen, and the other of R¹ or R² is an optionally substitutedC₁₋₄aliphatic group, wherein one or more methylene units in theC₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO—,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—. In still other embodiments,the optionally substituted C₁₋₄aliphatic group is substituted with Cy¹,wherein Cy¹ is 5-7-membered monocyclic aryl ring or an 8-10-memberedbicyclic aryl ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or is a 3-12 membered saturated orpartially unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, wherein Cy¹ isoptionally substituted with 0-5 independent occurrences of —R⁵. In yetother embodiments, one of R¹ or R² is hydrogen or C₁-C₄alkyl, and theother of R¹ or R² is —CH₂—Cy¹.

In yet other embodiments, for compounds of formula I-B, R¹ is anoptionally substituted C₁₋₄aliphatic group, wherein one or moremethylene units in the C₁₋₄aliphatic group are optionally replaced with—NR—, —O—, —COO—, —OCO, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—.

In still other embodiments, for compounds of formula I-A, neither R¹ norR² is hydrogen, and R¹ and R² are each independently selected from Cy¹,wherein Cy¹ is a 5-7-membered monocyclic aryl ring or an 8-10-memberedbicyclic aryl ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or is a 3-12-membered saturated, orpartially unsaturated monocyclic or bicyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, wherein Cy¹ isbonded directly to the nitrogen atom or is bonded through an optionallysubstituted C₁₋₄aliphatic group, wherein one or more methylene units inthe C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or from an optionallysubstituted C₁₋₄aliphatic group, wherein one or more methylene units inthe C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO—,—OCO—, —NRCO—, —CONR—, SO₂NR—, or —NRSO_(2.—) In other embodiments, bothR¹ and R² are an optionally substituted C₁₋₄aliphatic group, wherein oneor more methylene units in the C₁₋₄aliphatic group are optionallyreplaced with —NR—, —O—, —COO—, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or—NRSO_(2—).

In some embodiments, for compounds of formula I, I-A or I-B, Cy¹ isselected from:

wherein R⁴ is previously defined and z is 0-4. Other exemplary ringsinclude those shown below in Table 2.

In yet other embodiments, for compounds of formula I, I-A, and I-B,exemplary R¹ and R² groups are optionally substituted methyl, ethyl,cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH₂CH₃, (CH₂)₂OCH₃,CH₂(CO)OCH₂CH₃, CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, or n-butyl. Other exemplaryR¹ and R² groups include those shown below in Table 2.

In still other embodiments, for compounds of formula I-A, R¹ and R²,taken together with the nitrogen atom to which they are bound, form anoptionally substituted 3-12 membered heterocyclyl ring having 1-3heteroatoms independently selected from nitrogen, sulfur, or oxygen. Incertain preferred embodiments, R¹ and R² are taken together with thenitrogen atom to which they are bound and form a group selected from:

wherein the ring formed by R¹ and R² taken together, is optionallysubstituted at one or more substitutable carbon, nitrogen, or sulfuratoms with z independent occurrences of —R⁴, and z is 0-5.

In other embodiments, for compounds of formula I-A, R¹ and R² takentogether are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl(ff), piperidin1-yl (dd), piperazin-1-yl (cc), or morpholin-4-yl (ee).In other embodiments, for compounds of formula I-A, R¹ and R² takentogether are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl(ff), piperidin1-yl (dd), or piperazin-1-yl (cc). In yet otherembodiments, for compounds of formula I-A, R¹ and R², taken together isoptionally substituted azetidin-1-yl (jj). In yet other embodiments, forcompounds of formula I-A, R¹ and R², taken together is optionallysubstituted pyrrolidin-1-yl (ff). In still other embodiments, forcompounds of formula I-A, R¹ and R², taken together is optionallysubstituted piperidin 1-yl (dd). In yet other embodiments, for compoundsof formula I-A, R¹ and R², taken together is optionally substitutedpiperazin-1-yl (cc).

In certain embodiments, z is 0-2. In other embodiments, z is 0 and thering is unsubstituted. Preferred R⁴ groups, when present, are eachindependently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′,—SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′,—SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected fromC₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic,arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl. Other exemplary R⁴ groups are Cl, Br, F,CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃,—CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃,—SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂,—C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃,—C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted groupselected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl,phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or—CH₂thiazolyl. Still other exemplary R⁴ groups include those shown belowin Table 2.

In certain embodiments, for compounds of formula I-A, R¹ and R², takentogether is optionally substituted azetidin-1-yl (jj), wherein z is 1 or2 and at least one occurrence of R⁴ is —NRSO₂R′, —NRCOOR′, or —NRCOR′.In certain other embodiments, for compounds of formula I-A, R¹ and R²,taken together is optionally substituted azetidin-1-yl (jj), wherein zis 1 and R⁴ is —NRSO₂R′. In other embodiments, for compounds of formulaI-A, R¹ and R², taken together is optionally substituted azetidin-1-yl(jj), wherein z is 1 and R⁴ is —NRCOOR′. In certain other embodiments,for compounds of formula I-A, R¹ and R², taken together is optionallysubstituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRCOR′. In yetother embodiments, for compounds of formula I-A, R¹ and R², takentogether is optionally substituted pyrrolidin-1-yl (ff), wherein z is 1or 2 and R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In stillother embodiments, for compounds of formula I-A, R¹ and R², takentogether is optionally substituted piperidin-1-yl (dd), wherein z is 1or 2 and at least one occurrence of R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃,—OR′, or —CH₂OR′, —NRSO₂R′, —NRCOOR′, or —OCON(R′)₂. In certain otherembodiments, for compounds of formula I-A, R¹ and R², taken together isoptionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is F,CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In other embodiments, for compoundsof formula I-A, R¹ and R², taken together is optionally substitutedpiperidin-1-yl (dd), wherein z is 1 and R⁴ is —NRSO₂R′. In certain otherembodiments, for compounds of formula I-A, R¹ and R², taken together isoptionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is—NRCOOR′. In yet other embodiments, for compounds of formula I-A, R¹ andR², taken together is optionally substituted piperazin-1-yl (cc),wherein z is 1 or 2 and at least one occurrence of R⁴ is —SOR′,—CON(R′)₂, —SO₂N(R′)₂, —COR′, or —COOR′. In certain other embodiments,for compounds of formula I-A, R¹ and R², taken together is optionallysubstituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —SOR′. Incertain other embodiments, for compounds of formula I-A, R¹ and R²,taken together is optionally substituted piperazin-1-yl (cc), wherein zis 1 and R⁴ is —COOR′. In certain other embodiments, for compounds offormula I-A, R¹ and R², taken together is optionally substitutedpiperazin-1-yl (cc), wherein z is 1 and R⁴ is —CON(R′)₂. In certainother embodiments, for compounds of formula I-A, R¹ and R², takentogether is optionally substituted piperazin-1-yl (cc), wherein z is 1and R⁴ is —SO₂N(R′)₂. In certain other embodiments, for compounds offormula I-A, R¹ and R², taken together is optionally substitutedpiperazin-1-yl (cc), wherein z is 1 and R⁴ is —COR′.

As described generally above, for compounds of formulas I, I-A, or I-B,the quinazoline ring can be substituted with up to four independentoccurrences of R³. In certain embodiments, x is 0-2. In otherembodiments, x is 1 or 2. In still other embodiments x is 1 and R³ issubstituted at the 6- or 7-position of the quinazoline ring. When thequinazoline ring is substituted (x is 1-4), R³ groups are halogen, CN,NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′,—CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or anoptionally substituted group selected from C₁₋C₆aliphatic, aryl,heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl. In still other embodiments, eachoccurrence of R³ is independently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN,—COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃,—OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂,—CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substitutedgroup selected from -piperidinyl, piperizinyl, morpholino, phenyl,phenyloxy, benzyl, or benzyloxy. In still other embodiments, x is 1 or 2and each R³ group is independently halogen, CN, optionally substitutedC₁-C₆alkyl, OR′, N(R′)₂, CON(R′)₂, or NRCOR′. In yet other embodiments,x is 1 or 2, and each R³ group is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃,—CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or—CN. In still other embodiments, x is 1 and R³ is at the 6-position ofthe quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃,—CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or—CN. IN yet other embodiments, x is 1 and R³ is at the 7-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃,—CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In otherembodiments, x is 1 and R³ is at the 6-position of the quinazoline ringand is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In stillother embodiments, x is 1 and R³ is at the 7-position of the quinazolinering and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. Inother embodiments, x is 1 and R³ is at the 6-position of the quinazolinering and is —CON(R′)₂, or NRCOR′. In yet other embodiments, x is 1 andR³ is at the 7-position of the quinazoline ring and is —CON(R′)₂, orNRCOR′. Other exemplary R³ groups include those shown below in Table 2.

As described generally above, for compounds of formula I, I-A, or I-B,Ring A is a 5-7-membered monocyclic aryl ring or an 8-10-memberedbicyclic aryl ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or is a 3-12-membered saturated orpartially unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, wherein ring Ais optionally substituted with y independent occurrences of —R⁵, whereiny is 0-5, and is additionally optionally substituted with q independentoccurrences of R^(5a), wherein q is 0-2.

In certain embodiments, ring A is selected from:

In certain other embodiments, ring A is selected from optionallysubstituted phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, or pyrrol-1-yl.

In some embodiments, y is 0-5, q is 0-2, and R⁵ and R^(5a) groups, whenpresent, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂,—OR′, —CH₂OR′, —SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂, —S(O)₂N(R′)₂, —OCOR′,—COR′, —CO₂R′, —OCON(R′)₂, —NR′SO₂R′, —OP(O)(OR′)₂, —P(O)(OR′)₂,—OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, —OPO(R′)₂, or an optionally substitutedgroup selected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic,heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl,cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl

In yet other embodiments, y is 0-5, and q is 1 or 2, and each occurrenceof R^(5a) is independently Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂,—N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃,—OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃,—OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂,OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionallysubstituted benzyloxy.

In still other embodiments, y is 0, and q is 1 and R^(5a) is F. In yetother embodiments, y is 0, q is 1, and R^(5a) is OR′. In still otherembodiments, y is 0, q is 1 and R^(5a) is OH. In yet other embodiments,y is 0, q is 2 and one occurrence of R^(5a) is OR′ and the otheroccurrence of R^(5a) is F. In yet other embodiments, y is 0, q is 2 andone occurrence of R^(5a) is OH and the other occurrence of R^(5a) is F.

In still other embodiments, ring A is phenyl, y is 0, and q is 1 andR^(5a) is F substituted at the 2-position of the phenyl ring. In yetother embodiments, ring A is phenyl, y is 0, q is 1, and R^(5a) is OR′substituted at the 2-position of the phenyl ring. In still otherembodiments, ring A is phenyl, y is 0, q is 1 and R^(5a) is OHsubstituted at the 2-position of the phenyl ring. In yet otherembodiments, ring A is phenyl, y is 0, q is 2 and one occurrence ofR^(5a) is OR′ and the other occurrence of R^(5a) is F, wherein OR′ issubstituted at the 2-position of the phenyl ring and F is substituted atthe 6-position of the phenyl ring. In yet other embodiments, ring A isphenyl, y is 0, q is 2 and one occurrence of R^(5a) is OH and the otheroccurrence of R^(5a) is F, wherein OH is substituted at the 2-positionof the phenyl ring and F is substituted at the 6-position of the phenylring.

Other exemplary R⁵ and R^(5a) groups include those shown below in Table2.

For compounds described in this section above, in general, compounds areuseful as inhibitors of ion channels, preferably voltage gated sodiumchannels and N-type calcium channels. In certain exemplary embodiments,compounds of the invention are useful as inhibitors of NaV1.8. In otherembodiments, compounds of the invention are useful as inhibitors ofNaV1.8 and CaV2.2. In still other embodiments, compounds of theinvention are useful as inhibitors of CaV2.2. In yet other embodiments,compounds of the invention are useful as dual inhibitors of NaV1.8 and aTTX-sensitive ion channel such as NaV1.3 or NaV1.7.

Certain additional embodiments of compounds described generally aboveare described in more detail below. For example:

I. Compounds of formula IA:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R², taken together with the nitrogen atom to which they arebound, form an optionally substituted 3-12-membered monocyclic orbicyclic saturated, partially unsaturated, or fully unsaturated ringhaving 0-3 additional heteroatoms independently selected from nitrogen,sulfur, or oxygen; wherein the ring formed by R¹ and R² taken together,is optionally substituted at one or more substitutable carbon, nitrogen,or sulfur atoms with z independent occurrences of —R⁴, wherein z is 0-5;

Ring A is a 5-7-membered monocyclic aryl ring or an 8-10-memberedbicyclic aryl ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or is a 3-12-membered saturated orpartially unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, wherein ring Ais optionally substituted with y independent occurrences of —R⁵, whereiny is 0-5, and is additionally optionally substituted with q independentoccurrences of R^(5a), wherein q is 0-2;

x is 0-4;

each occurrence of R³, R⁴, and R⁵ is independently Q-R^(X); wherein Q isa bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacentmethylene units of Q are optionally and independently replaced by —NR—,—S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—,—SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—,—SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of R^(X)is independently selected from —R′, halogen, ═O, ═NR′, —NO₂, —CN, —OR′,—SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′,—CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′,—NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂,—OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂;

each occurrence of R^(5a) is independently an optionally substitutedC₁-C₆aliphatic group, halogen, —OR′, —SR′, —N(R′)₂, —NR′COR′,—NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂,—SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′,—COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂,or —OPO(R′)₂; and

each occurrence of R is independently hydrogen or an optionallysubstituted C₁₋₆aliphatic group; and each occurrence of R′ isindependently hydrogen or an optionally substituted C₁₋₆ aliphaticgroup, a 3-8-membered saturated, partially unsaturated, or fullyunsaturated monocyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an 8-12 memberedsaturated, partially unsaturated, or fully unsaturated bicyclic ringsystem having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrencesof R′, are taken together with the atom(s) to which they are bound toform an optionally substituted 3-12 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, for compounds described directly above:

a. when R¹ and R², taken together with the nitrogen atom to which theyare bound, form an optionally substituted 4-membered monocyclicsaturated or partially unsaturated ring having 0-3 additionalheteroatoms independently selected from nitrogen, sulfur, or oxygen;then 2-Oxazolidinone,3-[(3R,4R)-2-oxo-1-(2-phenyl-4-quinazolinyl)-4-[2-(3-pyridinyl)ethenyl]-3-azetidinyl]-4-phenyl-,(4S)— is excluded;

b. when R¹ and R², taken together with the nitrogen atom to which theyare bound, form an optionally substituted 5-membered monocyclicsaturated or partially unsaturated ring having 0-3 additionalheteroatoms independently selected from nitrogen, sulfur, or oxygen;then:

-   -   i. ring A is not optionally substituted        hexahydro-1H-1,4-diazepin-1-yl; and    -   ii. Benzenesulfonamide,        2-methoxy-5-[2-[[1-(2-phenyl-4-quinazolinyl)-3-pyrrolidinyl]amino]ethyl]-,        (R)—, bis(trifluoroacetate), and Benzenesulfonamide,        2-methoxy-5-[2-[[1-(2-phenyl-4-quinazolinyl)-3-pyrrolidinyl]amino]ethyl]-,        (S)—, bis(trifluoroacetate) are excluded;    -   iii. 3-Pyrrolidinamine, 1-(2-phenyl-4-quinazolinyl)-, and        (R)-3-Pyrrolidinamine, 1-(2-phenyl-4-quinazolinyl)-, (S)— are        excluded;    -   iv. when R¹ and R², taken together are unsubstituted        pyrrolidin-1-yl, ring A is unsubstituted phenyl, and x is 1,        then R³ is not 6-OMe or 6-OH;    -   v. when R¹ and R², taken together are unsubstituted        pyrrolidin-1-yl, ring A is unsubstituted phenyl, and x is 2,        then the two R³ groups are not 6-OMe and 7-OMe;    -   vi. when R¹ and R², taken together are unsubstituted        pyrrolidin-1-yl, then ring A is not unsubstituted        pyrrolidin-1-yl, optionally substituted piperazin-1-yl,        unsubstituted morpholin-1-yl; or unsubstituted piperidin-1-yl;    -   vii. when R¹ and R²; taken together are pyrrolidin-1-yl, x is 0        and ring A is unsubstituted phenyl, then the pyrrolidin-1-yl        group is not substituted at the 3-position with —OH or        2-methoxy-phenoxy;    -   viii. when R¹ and R², taken together are unsubstituted        pyrrolidin-1-yl, and x is 0, then ring A is not 2,3-xylyl,        3-methylphenyl, unsubstituted phenyl, 4-bromo-phenyl,        4-chloro-phenyl, 3-nitro-phenyl, unsubstituted pyrid-3-yl,        2,4-dichlorophenyl, 3,4-dichlorophenyl, 4-propoxyphenyl,        3-methylphenyl, 3,4,5-trimethoxyphenyl, 2-chlorophenyl,        unsubstituted pyrid-4-yl, 2-hydroxyphenyl, or        4-(1,1-dimethylethyl)phenyl;

c. when R¹ and R², taken together with the nitrogen atom to which theyare bound, form an optionally substituted 6-membered monocyclic orbicyclic saturated or partially unsaturated ring having 0-3 additionalheteroatoms independently selected from nitrogen, sulfur, or oxygen;then:

-   -   i. when R¹ and R², taken together form an unsubstituted        morpholino ring, and ring A is unsubstituted phenyl, then x is        not 0, or if x is 1 or 2, then R³ is not: 6-fluoro,        6,7-dimethoxy, 6-nitro, 6-AcHN—, 6-methox, 6-NH2, 6-OCHN—, 6-OH,        6-AcMeN—, 6-TsHN—, 6-Me2N—, 7-OH, 6-amino-thiazol-2-yl,        6-NHCOCOOEt, or 6-(4-phenyl-amino-thiazol-2-yl);    -   ii. when R¹ and R², taken together form an unsubstituted        morpholino ring, and ring A is unsubstituted cyclohexyl,        unsubstituted pyrid-3-yl, unsubstituted 2-furyl, 2-fluorophenyl,        3-thienyl, benzofuran, pyridazine, phenyl substituted in one or        more of the 3, 4, or 5-position of the phenyl ring, and x is 1        or 2, then R³ is not 6-NH2, 6-OHCHN—, 6-OH, 7-OH, 6-MsHN—,        6-AcHN—, 6-fluoro, or 6-OMe;    -   iii. when R¹ and R², taken together, form a piperid-4-one,        piperid-4-ol, or thiomorpholino, or a dimethyl substituted        morpholino ring, ring A is unsubstituted phenyl, and x is 1,        then R³ is not 6-OH;    -   iv. when x is 0 and A is unsubstituted phenyl,        3,4,5-trimethoxyphenyl, or 3,4-dimethoxyphenyl, then R¹ and R²,        taken together is not optionally substituted piperidinyl or        optionally substituted piperazinyl;    -   v. when x is 2 or 3, and R³ is 6,7-diOMe, or 6,7,8-triOMe, then        R¹ and R², taken together is not optionally substituted        piperidin-1-yl, piperazin-1-yl, or morpholin-1-yl;    -   vi. when x is 0 and ring A is unsubstituted phenyl, then R¹ and        R², taken together is not optionally substituted or fused        piperazinyl;    -   vii. when x is 0 and ring A is phenyl optionally substituted in        one or more of the 3-, 4-, or 5-positions of the phenyl ring,        then R¹ and R², taken together is not optionally substituted        piperazin-1-yl, or morpholin-1-yl;    -   viii. when x is 0 and ring A is 2-F-phenyl, then R¹ and R²,        taken together is not 4-(2-Cl-phenyl)-piperazin-1-yl,        4-(3-Cl-phenyl)-piperazin-1-yl, or unsubstituted morpholin-1-yl;    -   ix. when x is 0 and ring A is 2-Cl-phenyl, then R¹ and R², taken        together is not unsubstituted morpholin-1-yl,        4-Me-piperazin-1-yl, 4-Et-piperazin-1-yl,        4-phenyl-piperazin-1-yl, or 4-CH₂Ph₂-piperazin-1-yl;    -   x. when x is 0 and ring A is 2-OH-phenyl, then R1 and R2, taken        together is not unsubstituted morpholin-1-yl,        4-(2-OMe-phenyl)-piperazin-1-yl, 4-CH2Ph-piperazin-1-yl,        4-Et-piperazin-1-yl, or 4-Me-piperazin-1-yl;    -   xi. when x is 0, x is 1 and R³ is 6-Br, or x is 2 and R³ is        6-7-diOMe, and ring A is optionally substituted 2- or 3-thienyl,        then R¹ and R², taken together is not 4-Ph-piperazin-1-yl,        4-(3-CF₃-phenyl)-piperazin-1-yl,        4-(2-OEt-phenyl)-piperazin-1-yl, 4-Me-piperazinyl, or        unsubstituted morpholin-1-yl;    -   xii when x is 0, and ring A is unsubstituted pyrid-3-yl or        pyrid-4-yl, then R¹ and R², taken together is not optionally        substituted morpholin-1-yl, or optionally substituted        piperazin-1-yl;    -   xiii. when x is 0, and ring A is optionally substituted        1H-imidazol-2-yl or 1H-imidazol-1-yl, then R¹ and R² taken        together is not unsubstituted morpholin-1-yl,        4-Me-piperazin-1-yl, or 4-CH₂CH₂OH-piperazin-1-yl;    -   xiv. when x is 0 and ring A is 5-NO₂-thiazol-2-yl, then R¹ and        R², taken together is not 4-Me-piperazin-1-yl;    -   xv. when x is 0 and ring A is 5-NO₂-2-furanyl, then R¹ and R²,        taken together is not 4-CH₂CH₂OH-piperazin-1-yl,        4-Me-piperazin-1-yl, or unsubstituted morpholin-1-yl;    -   xvi. when x is 1, R³ is 6-OH and ring A is unsubstituted phenyl,        then R¹ and R², taken together is not unsubstituted        morpholin-1-yl, or 4-Me-piperazin-1-yl;    -   xvii. when x is 0 and R¹ and R², taken together is unsubstituted        piperidinyl, then ring A is not 2-OH-phenyl, 4-OMe-phenyl,        4-F-phenyl, 4-NO₂-phenyl, pyrid-3-yl, pyrid-4-yl, 2-Cl-phenyl,        4-O_(n)Pr-phenyl, 3,4-dichlorophenyl, 2-F-phenyl, 4-Br-phenyl,        4-Cl-phenyl, 3-NO₂-phenyl, or 2,4-dichlorophenyl;    -   xviii. when x is 0, ring A is 4-Br-phenyl, 2-F-phenyl,        2-Cl-phenyl, 4-Cl-phenyl, 4-OnPr-phenyl, 2,4-dichlorophenyl,        3,4-dichlorophenyl, 4-Me-phenyl, 3-Me-phenyl, pyrid-3-yl,        pyrid-4-yl, 2-OH-phenyl, 4-NO₂-phenyl, 4-tBu-phenyl, then R¹ and        R², taken together is not 2-Me-piperidin-1-yl,        4-CH₂-Ph-piperidin-1-yl, 4-Me-piperidin-1-yl,        3-COOEt-piperidin-1-yl, 4-COOEt-piperidin-1-yl,        2-Et-piperidin-1-yl, 3-Me-piperidin-1-yl,        3,5-diMe-piperidin-1-yl, 4-CONH₂-piperidin-1-yl, (4-piperidinyl,        4-carboxamide)-piperidin-1-yl, 1,4-dioxa-8-azaspiro[4.5]decane,        3,4-dihydro-2(1H)-isoquinolinyl, or piperidin-4-one;    -   xix. when x is 1, R³ is 6-Br, 6-Cl, 6-OH, 6-OMe, or 6-Me and        ring A is 4-bromophenyl, 4-CH₂P(O)(OH)(OEt)phenyl, or        unsubstituted phenyl, then R¹ and R², taken together, is not        optionally substituted piperidinyl;    -   xx. when x is 2, and R³ is 6,7-dimethoxy, and A is unsubstituted        phenyl, then R¹ and R², taken together is not        1,4-dioxa-8-azaspiro[4.5]decane or        3,4-dihydro-2(1H)-isoquinolinyl;    -   xxi. when x is 3, and the three occurrences of R³ are 5-OAc,        6-OAc, and 8-piperidinyl, and ring A is unsubstituted phenyl,        then R¹ and R², taken together is not an unsubstituted        piperidinyl ring;    -   xxii. when x is 3 and the three occurrences of R³ are 6-Me,        7-COOEt, and 8-Me, and ring A is 2-Cl-phenyl, then R¹ and R²,        taken together, is not 4-phenyl-piperidin-1-yl,        4-(4-Cl-phenyl)-piperazin-1-yl, unsubstituted piperazin-1-yl,        4-CH₂Ph-piperazin-1-yl, 4(2-Cl-phenyl)piperazin-1-yl, or        4-COOEt-piperazin-1-yl;

c. when R¹ and R², taken together with the nitrogen atom to which theyare bound, form an optionally substituted 7-membered monocyclic orbicyclic saturated or partially unsaturated ring having 0-3 additionalheteroatoms independently selected from nitrogen, sulfur, or oxygen;then:

-   -   i. Benzenesulfonamide,        2-methoxy-5-[2-[5-(2-phenyl-4-quinazolinyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethyl]-,        and bis(trifluoroacetate) 2,5-Diazabicyclo[2.2.1]heptane,        2-(2-phenyl-4-quinazolinyl)- are excluded;    -   ii. when x is 2 and both occurrences of R³ are OMe, and ring A        is 4-Cl-phenyl, then R¹ and R², taken together is not        unsubstituted hexahydro-1H-azepin-1-yl;    -   iii. when x is 0 and R¹ and R², taken together is unsubstituted        hexahydro-1H-azepin-1-yl, then ring A is not unsubstituted        phenyl, 4-F-phenyl, 4-NO₂-phenyl, pyrid-4-yl, 3,4-diCl-phenyl,        2-Cl-phenyl, 2,4-diCl-phenyl, 2,4-diCl-phenyl, 3-NO₂-phenyl,        4-Cl-phenyl, 4-O_(n)Pr-phenyl, 3-Me-phenyl, 3,4-OMe-phenyl,        3,4,5-OMe-phenyl, pyrid-3-yl, or 2-OH-phenyl;

d. when R¹ and R², taken together with the nitrogen atom to which theyare bound, form an optionally substituted 8-membered monocyclic orbicyclic saturated or partially unsaturated ring having 0-3 additionalheteroatoms independently selected from nitrogen, sulfur, or oxygen;then:

-   -   i. Benzenesulfonamide,        2-methoxy-5-[2-[8-(2-phenyl-4-quinazolinyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethyl]-,        bis(trifluoroacetate) 3,8-Diazabicyclo[3.2.1]octane,        3-(phenylmethyl)-8-(2-phenyl-4-quinazolinyl)-3,8-Diazabicyclo[3.2.1]octane,        8-(2-phenyl-4-quinazolinyl)-; Quinazoline,        2-(3-methylphenyl)-4-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)-,        monohydrochloride; Quinazoline,        2-(4-nitrophenyl)-4-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)-,        monohydrochloride; Quinazoline,        2-(3-methylphenyl)-4-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)-;        Quinazoline,        2-(4-methylphenyl)-4-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)-;        and Quinazoline,        2-(4-nitrophenyl)-4-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)-        are excluded; and

e. when R¹ and R², taken together with the nitrogen atom to which theyare bound, form an optionally substituted 9-membered monocyclic orbicyclic saturated or partially unsaturated ring having 0-3 additionalheteroatoms independently selected from nitrogen, sulfur, or oxygen;then: piperazine,1-[4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-6,7-dimethoxy-2-quinazolinyl]-4-(2-furanylcarbonyl)-is excluded.

In other embodiments, for compounds described directly above, the ringformed by R¹ and R² taken together is selected from:

wherein the ring formed by R¹ and R² taken together, is optionallysubstituted at one or more substitutable carbon, nitrogen, or sulfuratoms with z independent occurrences of —R⁴, and z is 0-5.

In other embodiments, for compounds of formula I-A, R¹ and R² takentogether are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl(ff), piperidin1-yl (dd), piperazin-1-yl (cc), or morpholin-4-yl (ee).In other embodiments, for compounds of formula I-A, R¹ and R² takentogether are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl(ff), piperidin1-yl (dd), or piperazin-1-yl (cc). In yet otherembodiments, for compounds of formula I-A, R¹ and R², taken together isoptionally substituted azetidin-1-yl (jj). In yet other embodiments, forcompounds of formula I-A, R¹ and R², taken together is optionallysubstituted pyrrolidin-1-yl (ff). In still other embodiments, forcompounds of formula I-A, R¹ and R², taken together is optionallysubstituted piperidin 1-yl (dd). In yet other embodiments, for compoundsof formula I-A, R¹ and R², taken together is optionally substitutedpiperazin-1-yl (cc).

For compounds described directly above, z is 0-5, and R⁴ groups, whenpresent, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂,—OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂,COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted groupselected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic,heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl,cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.

In still other embodiments, z is 0-5 and R⁴ groups are eachindependently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂,—N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃,—SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃,—C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃,—COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionallysubstituted group selected from -piperidinyl, piperizinyl, morpholino,C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl,pyridyl, —CH₂pyridyl, or —CH₂thiazolyl.

In certain embodiments, for compounds of formula I-A, R¹ and R², takentogether is optionally substituted azetidin-1-yl (jj), wherein z is 1 or2 and at least one occurrence of R⁴ is —NRSO₂R′, —NRCOOR′, or —NRCOR′.In certain other embodiments, for compounds of formula I-A, R¹ and R²,taken together is optionally substituted azetidin-1-yl (jj), wherein zis 1 and R⁴ is —NRSO₂R′. In other embodiments, for compounds of formulaI-A, R¹ and R², taken together is optionally substituted azetidin-1-yl(jj), wherein z is 1 and R⁴ is —NRCOOR′. In certain other embodiments,for compounds of formula I-A, R¹ and R², taken together is optionallysubstituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRCOR′. In yetother embodiments, for compounds of formula I-A, R¹ and R², takentogether is optionally substituted pyrrolidin-1-yl (ff), wherein z is 1or 2 and R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In stillother embodiments, for compounds of formula I-A, R¹ and R², takentogether is optionally substituted piperidin-1-yl (dd), wherein z is 1or 2 and at least one occurrence of R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃,—OR′, or —CH₂OR′, —NRSO₂R′, —NRCOOR′, or —OCON(R′)₂. In certain otherembodiments, for compounds of formula I-A, R¹ and R², taken together isoptionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is F,CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In other embodiments, for compoundsof formula I-A, R¹ and R², taken together is optionally substitutedpiperidin-1-yl (dd), wherein z is 1 and R⁴ is —NRSO₂R′. In certain otherembodiments, for compounds of formula I-A, R¹ and R², taken together isoptionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is—NRCOOR′. In yet other embodiments, for compounds of formula I-A, R¹ andR², taken together is optionally substituted piperazin-1-yl (cc),wherein z is 1 or 2 and at least one occurrence of R⁴ is —SOR′,—CON(R′)₂, —SO₂N(R′)₂, —COR′, or —COOR′. In certain other embodiments,for compounds of formula I-A, R¹ and R², taken together is optionallysubstituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —SOR′. Incertain other embodiments, for compounds of formula I-A, R¹ and R²,taken together is optionally substituted piperazin-1-yl (cc), wherein zis 1 and R⁴ is —COOR′. In certain other embodiments, for compounds offormula I-A, R¹ and R², taken together is optionally substitutedpiperazin-1-yl (cc), wherein z is 1 and R⁴ is —CON(R′)₂. In certainother embodiments, for compounds of formula I-A, R¹ and R², takentogether is optionally substituted piperazin-1-yl (cc), wherein z is 1and R⁴ is —SO₂N(R′)₂. In certain other embodiments, for compounds offormula I-A, R¹ and R², taken together is optionally substitutedpiperazin-1-yl (cc), wherein z is 1 and R⁴ is —COR′.

For compounds described directly above, in some embodiments, x is 0-4,and R³ groups, when present, are each independently halogen, CN, NO₂,—N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′,—CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or anoptionally substituted group selected from C₁₋C₆aliphatic, aryl,heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.

In yet other embodiments, x is 1 or 2, and each occurrence of R³ isindependently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂,—N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃,—CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃,—CONHCH₂CH₃, or an optionally substituted group selected from-piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, orbenzyloxy.

In still other embodiments, x is 1 or 2 and each R³ group isindependently halogen, CN, optionally substituted C₁-C₆alkyl, OR′,N(R′)₂, CON(R′)₂, or NRCOR′.

In yet other embodiments, x is 1 or 2, and each R³ group is —Cl, —CH₃,—CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl),—OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In still other embodiments, x is 1 and R³ is at the 6-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —CONHCH₃,—CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In yet other embodiments, x is 1 and R³ is at the 7-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃,—CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In still other embodiments, x is 1 and R³ is at the 6-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or—OCH₂CH₃.

In yet other embodiments, x is 1 and R³ is at the 7-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or—OCH₂CH₃.

In still other embodiments, x is 1 and R³ is at the 6-position of thequinazoline ring and is —CON(R′)₂, or NRCOR′.

In yet other embodiments, x is 1 and R³ is at the 7-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or—OCH₂CH₃.

For compounds described directly above, in certain embodiments, ring Ais a group selected from:

In other embodiments, ring A is optionally substituted phenyl,2-pyridyl, 3-pyridyl, or 4-pyridyl, or pyrrol-1-yl.

For compounds described directly above, in some embodiments, y is 0-5, qis 0-2, and R⁵ and R^(5a) groups, when present, are each independentlyhalogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′,—NRCOR′, —CON(R′)₂, —S(O)₂N(R′)₂, —OCOR′, —COR′, —CO₂R′, —OCON(R′)₂,—NR′SO₂R′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂,—OPO(R′)₂, or an optionally substituted group selected fromC₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic,arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.

In still other embodiments, y is 0-5, and q is 1 or 2, and eachoccurrence of R^(5a) is independently Cl, Br, F, CF₃, Me, Et, CN, —COOH,—NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH,—OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃,—OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂,OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionallysubstituted benzyloxy.

In still other embodiments, y is 0, and q is 1 and R^(5a) is F. In yetother embodiments, y is 0, q is 1, and R^(5a) is OR′. In still otherembodiments, y is 0, q is 1 and R^(5a) is OH. In yet other embodiments,y is 0, q is 2 and one occurrence of R^(5a) is OR′ and the otheroccurrence of R^(5a) is F. In yet other embodiments, y is 0, q is 2 andone occurrence of R^(5a) is OH and the other occurrence of R^(5a) is F.

In yet other embodiments, ring A is optionally substituted phenyl andcompounds have the structure IA-i:

wherein:

y is 0-5;

q is 0-2; and

each occurrence of R^(5a) is independently an optionally substitutedC₁-C₆aliphatic group, halogen, —OR′, —SR′, —N(R′)₂, —NR′COR′,—NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂,—SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′,—COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂,or —OPO(R′)₂.

In certain exemplary embodiments, the ring formed by R¹ and R² takentogether is selected from:

wherein the ring formed by R¹ and R² taken together, is optionallysubstituted at one or more substitutable carbon, nitrogen, or sulfuratoms with z independent occurrences of —R⁴, and z is 0-5.

In other embodiments, for compounds of formula IA-i, R¹ and R² takentogether are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl(ff), piperidin1-yl (dd), piperazin-1-yl (cc), or morpholin-4-yl (ee).In other embodiments, for compounds of formula I-A, R¹ and R² takentogether are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl(ff), piperidin1-yl (dd), or piperazin-1-yl (cc). In yet otherembodiments, for compounds of formula IA-i, R¹ and R², taken together isoptionally substituted azetidin-1-yl (jj). In yet other embodiments, forcompounds of formula IA-i, R¹ and R², taken together is optionallysubstituted pyrrolidin-1-yl (ff). In still other embodiments, forcompounds of formula IA-i, R¹ and R², taken together is optionallysubstituted piperidin1-yl (dd). In yet other embodiments, for compoundsof formula IA-i, R¹ and R², taken together is optionally substitutedpiperazin-1-yl (cc).

For compounds of formula IA-i, z is 0-5, and R⁴ groups, when present,are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′,—CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′,—NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted groupselected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic,heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl,cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl. In otherembodiments, z is 0-5 and R⁴ groups are each independently Cl, Br, F,CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃,—CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃,—SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂,—C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃,—C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted groupselected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl,phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or—CH₂thiazolyl.

In certain embodiments, for compounds of formula IA-i, R¹ and R², takentogether is optionally substituted azetidin-1-yl (jj), wherein z is 1 or2 and at least one occurrence of R⁴ is —NRSO₂R′, —NRCOOR′, or —NRCOR′.In certain other embodiments, for compounds of formula IA-i, R¹ and R²,taken together is optionally substituted azetidin-1-yl (jj), wherein zis 1 and R⁴ is —NRSO₂R′. In other embodiments, for compounds of formulaIA-i, R¹ and R², taken together is optionally substituted azetidin-1-yl(jj), wherein z is 1 and R⁴ is —NRCOOR′. In certain other embodiments,for compounds of formula IA-i, R¹ and R², taken together is optionallysubstituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRCOR′. In yetother embodiments, for compounds of formula IA-i, R¹ and R², takentogether is optionally substituted pyrrolidin-1-yl (ff), wherein z is 1or 2 and R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In stillother embodiments, for compounds of formula IA-i, R¹ and R², takentogether is optionally substituted piperidin-1-yl (dd), wherein z is 1or 2 and at least one occurrence of R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃,—OR′, or —CH₂OR′, —NRSO₂R′, —NRCOOR′, or —OCON(R′)₂. In certain otherembodiments, for compounds of formula IA-i, R¹ and R², taken together isoptionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is F,CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In other embodiments, for compoundsof formula IA-i, R¹ and R², taken together is optionally substitutedpiperidin-1-yl (dd), wherein z is 1 and R⁴ is —NRSO₂R′. In certain otherembodiments, for compounds of formula IA-i, R¹ and R², taken together isoptionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is—NRCOOR′. In yet other embodiments, for compounds of formula IA-i, R¹and R², taken together is optionally substituted piperazin-1-yl (cc),wherein z is 1 or 2 and at least one occurrence of R⁴ is —SOR′,—CON(R′)₂, —SO₂N(R′)₂, —COR′, or —COOR′. In certain other embodiments,for compounds of formula IA-i, R¹ and R², taken together is optionallysubstituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —SOR′. Incertain other embodiments, for compounds of formula IA-i, R¹ and R²,taken together is optionally substituted piperazin-1-yl (cc), wherein zis 1 and R⁴ is —COOR′. In certain other embodiments, for compounds offormula IA-i, R¹ and R², taken together is optionally substitutedpiperazin-1-yl (cc), wherein z is 1 and R⁴ is —CON(R′)₂. In certainother embodiments, for compounds of formula IA-i, R¹ and R², takentogether is optionally substituted piperazin-1-yl (cc), wherein z is 1and R⁴ is —SO₂N(R′)₂. In certain other embodiments, for compounds offormula IA-i, R¹ and R², taken together is optionally substitutedpiperazin-1-yl (cc), wherein z is 1 and R⁴ is —COR′.

In some embodiments for compounds of formula IA-i, x is 0-4, and R³groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂,—CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂,—OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionallysubstituted group selected from C₁₋C₆aliphatic, aryl, heteroaryl,cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.

In still other embodiments, x is 1 or 2, and each occurrence of R³ isindependently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂,—N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃,—CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃,—CONHCH₂CH₃, or an optionally substituted group selected from-piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, orbenzyloxy.

In yet other embodiments, x is 1 or 2 and each R³ group is independentlyhalogen, CN, optionally substituted C₁-C₆alkyl, OR′, N(R′)₂, CON(R′)₂,or NRCOR′.

In still other embodiments, x is 1 or 2, and each R³ group is —Cl, —CH₃,—CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl),—OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In yet other embodiments x is 1 and R³ is at the 6-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃,—CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In still other embodiments, x is 1 and R³ is at the 7-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃,—CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In yet other embodiments, x is 1 and R³ is at the 6-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or—OCH₂CH₃.

In still other embodiments, x is 1 and R³ is at the 7-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or—OCH₂CH₃.

In yet other embodiments, x is 1 and R³ is at the 6-position of thequinazoline ring and is —CON(R′)₂, or NRCOR′.

In still other embodiments, x is 1 and R³ is at the 7-position of thequinazoline ring and is —CON(R′)₂, or NRCOR′.

In some embodiments for compounds of formula IA-i, y is 0-5, q is 0-2,and R⁵ and R^(5a) groups, when present, are each independently halogen,CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —NRCOR′,—CON(R′)₂, —S(O)₂N(R′)₂, —OCOR′, —COR′, —CO₂R′, —OCON(R′)₂, —NR′SO₂R′,—OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, —OPO(R′)₂,or an optionally substituted group selected from C₁-C₆aliphatic, aryl,heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.

In yet other embodiments, y is 0-5, and q is 1 or 2, and each occurrenceof R^(5a) is independently Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂,—N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃,—OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃,—OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂,OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionallysubstituted benzyloxy.

In still other embodiments, when ring A is phenyl, y is 0, and q is 1and R^(5a) is F substituted at the 2-position of the phenyl ring. In yetother embodiments, when ring A is phenyl, y is 0, q is 1, and R^(5a) isOR′ substituted at the 2-position of the phenyl ring. In still otherembodiments, when ring A is phenyl, y is 0, q is 1 and R^(5a) is OHsubstituted at the 2-position of the phenyl ring. In yet otherembodiments, when ring A is phenyl, y is 0, q is 2 and one occurrence ofR^(5a) is OR′ and the other occurrence of R^(5a) is F, wherein OR′ issubstituted at the 2-position of the phenyl ring and F is substituted atthe 6-position of the phenyl ring. In yet other embodiments, when ring Ais phenyl, y is 0, q is 2 and one occurrence of R^(5a) is OH and theother occurrence of R^(5a) is F, wherein OH is substituted at the2-position of the phenyl ring and F is substituted at the 6-position ofthe phenyl ring.

In still other embodiments, for compounds of formula IA-i, q is 1 andR^(5a) is at the 2-position of the phenyl ring, and compounds have thestructure IA-ii:

wherein:

a) the ring formed by R¹ and R² taken together is selected from:

and the ring formed by R¹ and R² taken together, is optionallysubstituted at one or more substitutable carbon, nitrogen, or sulfuratoms with z independent occurrences of —R⁴, and z is 0-5;

b) wherein z is 0-5, and R⁴ groups, when present, are each independentlyhalogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′,—COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′,—SO₂N(R′)₂, or an optionally substituted group selected fromC₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic,arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.

c) wherein x is 0-4, and R³ groups, when present, are each independentlyhalogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′,—COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′,—SO₂N(R′)₂, or an optionally substituted group selected fromC₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic,arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.

d) wherein y is 0-5, and R⁵ groups, when present, are each independentlyhalogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′,—NRCOR′, —CON(R′)₂, —S(O)₂N(R′)₂, —OCOR′, —COR′, —CO₂R′, —OCON(R′)₂,—NR′SO₂R′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂,—OPO(R′)₂, or an optionally substituted group selected fromC₁-C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic,arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl; and

e) R^(5a) is Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂,—N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH,—NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃,—O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl),—COCH₃, optionally substituted phenoxy, or optionally substitutedbenzyloxy.

In still other embodiments, for compounds of formula IA-ii: q is 1 andR^(5a) is at the 2-position of the phenyl ring, and compounds have thestructure IA-ii:

wherein:

a) R¹ and R² taken together is an optionally substituted ring selectedfrom azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidin1-yl (dd), orpiperazin-1-yl (cc);

b) z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃,—CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂,—COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂,—SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂,—NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, oran optionally substituted group selected from -piperidinyl, piperizinyl,morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy,—CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl;

c) x is 1 or 2, and each occurrence of R³ is independently Cl, Br, F,CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂,—O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃,—NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or anoptionally substituted group selected from -piperidinyl, piperizinyl,morpholino, phenyl, phenyloxy, benzyl, or benzyloxy;

d) wherein y is 0-4, and R⁵ groups, when present, are each independentlyCl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂,—O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃,—SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂,4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), —COCH₃, optionallysubstituted phenoxy, or optionally substituted benzyloxy; and

e) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —SO₂NH₂,—SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂,4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or —COCH₃.

In still other embodiments, for compounds of formula IA-ii x is 1 and R³is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃,—F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂,—OCH₂CH₃, or —CN. In yet other embodiments, x is 1 and R³ is at the7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃,or —CN. In still other embodiments, x is 1 and R³ is at the 6-positionof the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃,—OCH₃, or —OCH₂CH₃. In yet other embodiments, x is 1 and R³ is at the7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —OCH₃, or —OCH₂CH₃. In still other embodiments, x is 1 and R³ isat the 6-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′.

In yet other embodiments, x is 1 and R³ is at the 7-position of thequinazoline ring and is —CON(R′)₂, or NRCOR′.

In still other embodiments, R^(5a) is Cl, F, CF₃, Me, Et, OR′, —OH,—OCH₃, —OCH₂CH₃.

In yet other embodiments, R^(5a) is OR′. In still other embodiments,R^(5a) is F.

In still other exemplary embodiments compounds have formula IA-ii:

wherein:

a) R¹ and R² taken together is an optionally substituted ring selectedfrom azetidin-1-yl (jj), pyrrolidin-1-yl piperidin1-yl (dd), orpiperazin-1-yl (cc);

b) z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃,—CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂,—COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂,—SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂,—NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, oran optionally substituted group selected from -piperidinyl, piperizinyl,morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy,—CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl;

c) x is 1, and each occurrence of R³ is independently Cl, Br, F, CF₃,—OCF₃, Me, Et, CN, —COOH, —OH, or —OCH₃;

d) y is 0 or 1, and R⁵ groups, when present, are each independently Cl,Br, F, CF₃, Me, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂,—SO₂NHC(CH₃)₂; and

e) R^(5a) is F, —OR′, or NHSO₂R′.

In some embodiments for compounds described directly above, x is 1 andR³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃,—CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl),—OCH₃, —NH₂, —OCH₂CH₃, or —CN. In still other embodiments, x is 1 and R³is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃,—F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂,—OCH₂CH₃, or —CN. In yet other embodiments, x is 1 and R³ is at the6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —OCH₃, or —OCH₂CH₃. In still other embodiments, x is 1 and R³ isat the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F,—CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In yet other embodiments, x is 1 and R³is at the 6-position of the quinazoline ring and is —CON(R′)₂, orNRCOR′. In still other embodiments, x is 1 and R³ is at the 7-positionof the quinazoline ring and is —CON(R′)₂; or NRCOR′.

In yet other embodiments, R^(5a) is OR′ and x is 1 and R³ is at the6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —OCH₃, or —OCH₂CH₃. In yet other embodiments, R^(5a) is OR′ and xis 1 and R³ is at the 7-position of the quinazoline ring and is —Cl,—CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.

In yet other embodiments, R^(5a) is OH and x is 1 and R³ is at the6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —OCH₃, or —OCH₂CH₃. In yet other embodiments, R^(5a) is OH and xis 1 and R³ is at the 7-position of the quinazoline ring and is —Cl,—CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.

In yet other embodiments, R^(5a) is F and x is 1 and R³ is at the6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —OCH₃, or —OCH₂CH₃. In yet other embodiments, R^(5a) is F and xis 1 and R³ is at the 7-position of the quinazoline ring and is —Cl,—CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.

In still other embodiments, for compounds of formula IA-ii, R¹ and R²,taken together is optionally substituted azetidin-1-yl (jj). In yetother embodiments, for compounds of formula IA-ii, R¹ and R², takentogether is optionally substituted pyrrolidin-1-yl (ff). In still otherembodiments, for compounds of formula IA-ii, R¹ and R², taken togetheris optionally substituted piperidin 1-yl (dd). In yet other embodiments,for compounds, of formula IA-ii, R¹ and R², taken together is optionallysubstituted piperazin-1-yl (cc).

In certain embodiments, for compounds of formula IA-ii, R¹ and R², takentogether is optionally substituted azetidin-1-yl (jj), wherein z is 1 or2 and at least one occurrence of R⁴ is —NRSO₂R′, —NRCOOR′, or —NRCOR′.In certain other embodiments, for compounds of formula IA-ii, R¹ and R²,taken together is optionally substituted azetidin-1-yl (jj), wherein zis 1 and R⁴ is —NRSO₂R′. In other embodiments, for compounds of formulaIA-ii, R¹ and R², taken together is optionally substituted azetidin-1-yl(jj), wherein z is 1 and R⁴ is —NRCOOR′. In certain other embodiments,for compounds of formula IA-ii, R¹ and R², taken together is optionallysubstituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRCOR′. In yetother embodiments, for compounds of formula IA-ii, R¹ and R², takentogether is optionally substituted pyrrolidin-1-yl (ff), wherein z is 1or 2 and R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In stillother embodiments, for compounds of formula IA-ii, R¹ and R², takentogether is optionally substituted piperidin-1-yl (dd), wherein z is 1or 2 and at least one occurrence of R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃,—OR′, or —CH₂OR′, —NRSO₂R′, —NRCOOR′, or —OCON(R′)₂. In certain otherembodiments, for compounds of formula IA-ii, R¹ and R², taken togetheris optionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ isF, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In other embodiments, forcompounds of formula IA-ii, R¹ and R², taken together is optionallysubstituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is —NRSO₂R′. Incertain other embodiments, for compounds of formula IA-ii, R¹ and R²,taken together is optionally substituted piperidin-1-yl (dd), wherein zis 1 and R⁴ is —NRCOOR′. In yet other embodiments, for compounds offormula IA-ii, R¹ and R², taken together is optionally substitutedpiperazin-1-yl (cc), wherein z is 1 or 2 and at least one occurrence ofR⁴ is —SOR′, —CON(R′)₂, —SO₂N(R′)₂, —COR′, or —COOR′. In certain otherembodiments, for compounds of formula IA-ii, R¹ and R², taken togetheris optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is—SOR′. In certain other embodiments, for compounds of formula IA-ii, R¹and R², taken together is optionally substituted piperazin-1-yl (cc),wherein z is 1 and R⁴ is —COOR′. In certain other embodiments, forcompounds of formula IA-ii, R¹ and R², taken together is optionallysubstituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —CON(R′)₂. Incertain other embodiments, for compounds of formula IA-ii, R¹ and R²,taken together is optionally substituted piperazin-1-yl (cc), wherein zis 1 and R⁴ is —SO₂N(R′)₂. In certain other embodiments, for compoundsof formula IA-ii, R¹ and R², taken together is optionally substitutedpiperazin-1-yl (cc), wherein z is 1 and R⁴ is —COR′.

For compounds described in this section above, in general, compounds areuseful as inhibitors of ion channels, preferably voltage gated sodiumchannels and N-type calcium channels. In certain exemplary embodiments,compounds of the invention are useful as inhibitors of NaV1.8. In otherembodiments, compounds of the invention are useful as inhibitors ofNaV1.8 and CaV2.2. In still other embodiments, compounds of theinvention are useful as inhibitors of CaV2.2. In yet other embodiments,compounds of the invention are useful as dual inhibitors of NaV1.8 and aTTX-sensitive ion channel such as NaV1.3 or NaV1.7.

II. Compounds of Formula IA-ii

wherein R¹ and R² are each independently an optionally substituted groupselected from C₁₋₆aliphatic, Cy¹, wherein Cy¹ is a 5-7-memberedmonocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, oris a 3-12-membered saturated or partially unsaturated monocyclic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, wherein Cy¹ is bonded directly to the nitrogen atom or is bondedthrough an optionally substituted C₁₋₄aliphatic group, wherein one ormore methylene units in the C₁₋₄aliphatic group are optionally replacedwith —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—;wherein R¹ and R² are each optionally and independently substituted atone or more substitutable carbon, nitrogen, or sulfur atoms with zindependent occurrences of —R⁴, wherein z is 0-5;

x is 0-4;

y is 0-4;

each occurrence of R³, R⁴, and R⁵ is independently Q-R^(X); wherein Q isa bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacentmethylene units of Q are optionally and independently replaced by —NR—,—S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—,—SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—,—SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of R^(X)is independently selected from —R′, ═O, ═NR′, halogen, —NO₂, —CN, —OR′,—SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′,—CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′,—NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂,—OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂;

R^(5a) is an optionally substituted C₁-C₆aliphatic group, halogen, —OR′,—SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′,—CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′,—NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂,—OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂; and

each occurrence of R is independently hydrogen or an optionallysubstituted C₁₋₆ aliphatic group; and each occurrence of R′ isindependently hydrogen or an optionally substituted C₁₋₆ aliphaticgroup, a 3-8-membered saturated, partially unsaturated, or fullyunsaturated monocyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an 8-12 memberedsaturated, partially unsaturated, or fully unsaturated bicyclic ringsystem having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrencesof R′, are taken together with the atom(s) to which they are bound toform an optionally substituted 3-12 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, for compounds described directly above,

a. when x is 0, R¹ is hydrogen, and R^(5a) is Cl, Me, CF₃, Br, or F,then R² is not —(CH₂)₂-4-Cy¹, —SO₂CH₂Cy¹, or —CH₂SO₂Cy¹, wherein Cy¹ isa 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic arylring having 0-3 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or is a 3-8-membered saturated or partiallyunsaturated monocyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur;

b. when x is 0, and R^(5a) is Cl, Me, NO₂, or OH, then:

-   -   i. when R¹ is hydrogen, R² is not Me, iBu, nBu, —COCH₃,        —CH₂COOEt, —CH₂COOMe, —CH₂CH₂OH, iPr, —CH₂-pyridyl, —CH₂Ph,        —(CH₂)₃NH₂, —(CH₂)₂-moropholinyl, or —CH₂CH₂Ph;    -   ii. R¹ and R² are not simultaneously Et or Me; and    -   iii. when R¹ is Et, then R² is not 4-Me-phenyl, 4-OMe-phenyl, or        2-Me-phenyl;

c. when x is 1 and R³ is 6-Cl, or 7-F, or x is 0 and R^(5a) is —OPr_(n),or Cl, then when R¹ is hydrogen, R² is not —(CH₂)₂-morpholino, or—CH₂(benzofuran); and

d. when x is 2 and one occurrence of R³ is 6-OMe and the otheroccurrence of R³ is 7-OMe, and R^(5a) is F, then when R¹ is hydrogen, R²is not —(CH₂)₃N(CH₃)₂;

In certain other embodiments, for compounds described directly above,

a) one of R¹ or R² is hydrogen, and the other of R¹ and R² is selectedfrom:

-   -   i) Cy¹ wherein Cy¹ is bonded directly to the nitrogen atom or is        bonded through an optionally substituted C₁₋₄aliphatic group,        wherein one or more methylene units in the C₁₋₄aliphatic group        are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—,        —CONR—, —SO₂NR—, or —NRSO₂—; or    -   ii) an optionally substituted C₁₋₄aliphatic group, wherein one        or more methylene units, in the C₁₋₄aliphatic group are        optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—,        —SO₂NR—, or —NRSO₂—; or

b) R¹ and R² are each independently selected from Cy¹, wherein Cy¹ isbonded directly to the nitrogen atom or is bonded through an optionallysubstituted C₁₋₄aliphatic group, wherein one or more methylene units inthe C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or an optionally substitutedC₁₋₄aliphatic group, wherein one or more methylene units in theC₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO—,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—.

In other embodiments Cy¹ is:

In still other embodiments, for compounds described directly above, R¹is hydrogen or an optionally substituted C₁-C₄aliphatic group and R² is—CHR-Cy¹, wherein R is hydrogen or C₁-C₄alkyl, and Cy¹ is:

In yet other embodiments, R¹ and R² groups are each independently anoptionally substituted C₁₋₄aliphatic group and are each independentlyselected from optionally substituted methyl, ethyl, cyclopropyl,n-propyl, propenyl, cyclobutyl, (CO)OCH₂CH₃, (CH₂)₂OCH₃, CH₂CO)OCH₂CH₃,CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, or n-butyl.

For compounds described directly above, z is 0-5, and R⁴ groups, whenpresent, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂,—OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂,COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted groupselected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic,heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl,cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.

In other embodiments, z is 0-5 and R⁴ groups are each independently Cl,Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂,—O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂,—SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂,—C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃,—C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted groupselected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl,phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or—CH₂thiazolyl.

In still other embodiments, for compounds described directly above, x is0-4, and R³ groups, when present, are each independently halogen, CN,NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′,—CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or anoptionally substituted group selected from C₁-C₆aliphatic, aryl,heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.

In yet other embodiments, for compounds described directly above, x is 1or 2, and each occurrence of R³ is independently Cl, Br, F, CF₃, —OCF₃,Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃,—CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂,—SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionallysubstituted group selected from -piperidinyl, piperizinyl, morpholino,phenyl, phenyloxy, benzyl, or benzyloxy.

In still other embodiments, x is 1 or 2 and each R³ group isindependently halogen, CN, optionally substituted C₁-C₆alkyl, OR′,N(R′)₂, CON(R′)₂, or NRCOR′.

In yet other embodiments, x is 1 or 2, and each R³ group is —Cl, —CH₃,—CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl),—OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In still other embodiments, x is 1 and R³ is at the 6-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃,—CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In yet other embodiments, x is 1 and R³ is at the 7-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃,—CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In still other embodiments, x is 1 and R³ is at the 6-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or—OCH₂CH₃.

In other embodiments, x is 1 and R³ is at the 7-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or—OCH₂CH₃.

In yet other embodiments, R³ is at the 6-position of the quinazolinering and is —CON(R′)₂, or NRCOR′.

In still other embodiments, x is 1 and R³ is at the 7-position of thequinazoline ring and is —CON(R′)₂, or NRCOR′.

For compounds described directly above, y is 0-4, q is 0-2, and R⁵ andR^(5a) groups, when present, are each independently halogen, CN, NO₂,—N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂,—S(O)₂N(R′)₂, —OCOR′, —COR′, —CO₂R′, —OCON(R′)₂, —NR′SO₂R′,—OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, —OPO(R′)₂,or an optionally substituted group selected from C₁₋C₆aliphatic, aryl,heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl

In other embodiments, y is 0-4, and q is 1 or 2, and each occurrence ofR^(5a) is independently Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂,—N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃,—OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃,—OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂,OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionallysubstituted benzyloxy.

In still other embodiments, y is 0, and R^(5a) is F. In yet otherembodiments, y is 0, q is 1, and R^(5a) is OR′. In still otherembodiments, y is 0, q is 1 and R^(5a) is OH. In yet other embodiments,y is 1, R^(5a) is OR′ and R⁵ is F, wherein OR′ is substituted at the2-position of the phenyl ring and F is substituted at the 6-position ofthe phenyl ring. In yet other embodiments, y is 1, R^(5a) is OH and R⁵is F, wherein OH is substituted at the 2-position of the phenyl ring andF is substituted at the 6-position of the phenyl ring.

In still other embodiments for compounds of formula IA-ii describeddirectly above:

a) one of R¹ or R² is hydrogen, and the other of R¹ and R² is selectedfrom Cy¹, wherein Cy¹ is bonded directly to the nitrogen atom or isbonded through an optionally substituted C₁₋₄aliphatic group, whereinone or more methylene units in the C₁₋₄aliphatic group are optionallyreplaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or—NRSO₂—, or an optionally substituted C₁₋₄aliphatic group, wherein oneor more methylene units in the C₁₋₄aliphatic group are optionallyreplaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or—NRSO₂—; or R¹ and R² are each independently selected from an optionallysubstituted C₁₋₄aliphatic group, wherein one or more methylene units inthe C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or Cy¹ wherein Cy¹ is bondedto the nitrogen atom directly or is bonded through an optionallysubstituted C₁₋₄aliphatic group, wherein one or more methylene units inthe C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—;

b) z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃,—CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂,—COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂,—SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂,—NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, oran optionally substituted group selected from -piperidinyl, piperizinyl,morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy,—CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl;

c) x is 0, 1, or 2, and each occurrence of R³ is independently Cl, Br,F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂,—O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃,—NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or anoptionally substituted group selected from -piperidinyl, piperizinyl,morpholino, phenyl, phenyloxy, benzyl, or benzyloxy;

d) wherein y is 0-4, and R⁵ groups, when present, are each independentlyCl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂,—O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃,—SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂,4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), —COCH₃, optionallysubstituted phenoxy, or optionally substituted benzyloxy; and

e) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —SO₂NH₂,—SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂,4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or —COCH₃.

In other embodiments, for compounds described directly above, x is 1 andR³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃,—CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl),—OCH₃, —NH₂, —OCH₂CH₃, or —CN. In yet other embodiments, x is 1 and R³is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃,—F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂,—OCH₂CH₃, or —CN. In still other embodiments, x is 1 and R³ is at the6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —OCH₃, or —OCH₂CH₃. In still other embodiments, x is 1 and R³ isat the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F,—CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In yet other embodiments, x is 1 and R³is at the 6-position of the quinazoline ring and is —CON(R′)₂, orNRCOR′.

In still other embodiments, x is 1 and R³ is at the 7-position of thequinazoline ring and is —CON(R′)₂, or NRCOR′.

In yet other embodiments, R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃,—OCH₂CH₃.

In still other embodiments, y is 0, and R^(5a) is F. In yet otherembodiments, y is 0, q is 1, and R^(5a) is OR′. In still otherembodiments, y is 0, q is 1 and R^(5a) is OH. In yet other embodiments,y is 1, R^(5a) is OR′ and R⁵ is F, wherein OR′ is substituted at the2-position of the phenyl ring and F is substituted at the 6-position ofthe phenyl ring. In yet other embodiments, y is 1, R^(5a) is OH and R⁵is F, wherein OH is substituted at the 2-position of the phenyl ring andF is substituted at the 6-position of the phenyl ring.

In still other embodiments for compounds of formula IA-ii describedabove:

a): one of R¹ or R² is hydrogen, and the other of R¹ and R² is selectedfrom Cy¹, wherein Cy¹ is bonded directly to the nitrogen atom or isbonded through an optionally substituted C₁₋₄aliphatic group, whereinone or more methylene units in the C₁₋₄aliphatic group are optionallyreplaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or—NRSO₂—, or an optionally substituted C₁₋₄aliphatic group, wherein oneor more methylene units in the C₁₋₄aliphatic group are optionallyreplaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or—NRSO₂—; or R¹ and R² are each independently selected from an optionallysubstituted C₁₋₄aliphatic group, wherein one or more methylene units inthe C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or Cy¹ wherein Cy¹ is bondedto the nitrogen atom directly or is bonded through an optionallysubstituted C₁₋₄aliphatic group, wherein one or more methylene units inthe C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; and Cy¹ is selected from:

or R¹ and R² are each independently an optionally substitutedC₁₋₄aliphatic group and are each independently selected from optionallysubstituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl,(CO)OCH₂CH₃, (CH₂)₂OCH₃, CH₂CO)OCH₂CH₃, CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, orn-butyl;

b) z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃,—CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂,—COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂,—SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂,—NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, oran optionally substituted group selected from -piperidinyl, piperizinyl,morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy,—CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl;

c) x is 0, 1, or 2, and each occurrence of R³ is independently Cl, Br,F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂,—O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃,—NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or anoptionally substituted group selected from -piperidinyl, piperizinyl,morpholino, phenyl, phenyloxy, benzyl, or benzyloxy;

d) wherein y is 0-4, and R⁵ groups, when present, are each independentlyCl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂,—O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃,—SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂,OCOCH(CH₃)₂, OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy,or optionally substituted benzyloxy; and

e) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —SO₂NH₂,—SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂,4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or —COCH₃.

In yet other embodiments for compounds described directly above, x is 1and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃,—CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl),—OCH₃, —NH₂, —OCH₂CH₃, or —CN. In still other embodiments, x is 1 and R³is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃,—F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂,OCH₂CH₃, or —CN. In still other embodiments, x is 1 and R³ is at the6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —OCH₃, or —OCH₂CH₃. In yet other embodiments, x is 1 and R³ is atthe 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F,—CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In still other embodiments, x is 1 andR³ is at the 6-position of the quinazoline ring and is —CON(R′)₂, orNRCOR′. In yet other embodiments,

x is 1 and R³ is at the 7-position of the quinazoline ring and is—CON(R′)₂, or NRCOR′. In still other embodiments, R^(5a) is Cl, F, CF₃,Me, Et, —OH, —OCH₃, —OCH₂CH₃.

In still other embodiments, y is 0, and R^(5a) is F. In yet otherembodiments, y is 0, q is 1, and R^(5a) is OR′. In still otherembodiments, y is 0, q is 1 and R^(5a) is OH. In yet other embodiments,y is 1, R^(5a) is OR′ and R⁵ is F, wherein OR′ is substituted at the2-position of the phenyl ring and F is substituted at the 6-position ofthe phenyl ring. In yet other embodiments, y is 1, R^(5a) is OH and R⁵is F, wherein OH is substituted at the 2-position of the phenyl ring andF is substituted at the 6-position of the phenyl ring.

For compounds described in this section above, in general, compounds areuseful as inhibitors of ion channels, preferably voltage gated sodiumchannels and N-type calcium channels. In certain exemplary embodiments,compounds of the invention are useful as inhibitors of NaV1.8. In otherembodiments, compounds of the invention are useful as inhibitors ofNaV1.8 and CaV2.2. In still other embodiments, compounds of theinvention are useful as inhibitors of CaV2.2. In yet other embodiments,compounds of the invention are useful as dual inhibitors of NaV1.8 and aTTX-sensitive ion channel such as NaV1.3 or NaV1.7.

III. Compounds of Formula IA-i

or a pharmaceutically acceptable salt thereof,

wherein R¹ and R² are each independently an optionally substituted groupselected from C₁₋₆aliphatic, Cy¹, wherein Cy¹ is a 5-7-memberedmonocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, oris a 3-12-membered saturated or partially unsaturated monocyclic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, wherein Cy¹ is bonded directly to the nitrogen atom or is bondedthrough an optionally substituted C₁₋₄aliphatic group, wherein one ormore methylene units in the C₁₋₄aliphatic group are optionally replacedwith —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—;wherein R¹ and R², are each optionally and independently substituted atone or more substitutable carbon, nitrogen, or sulfur atoms with zindependent occurrences of —R⁴, wherein z is 0-5;

x is 1 and R³ is substituted at either the 6- or 7-position of thequinazoline ring;

y is 0-4;

q is 0, 1 or 2;

each occurrence of R³, R⁴, and R⁵ is independently Q-R^(X); wherein Q isa bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacentmethylene units of Q are optionally and independently replaced by —NR—,—S—, —O—, —CS—, —CO₂—, —OCO, —CO—, —COCO—, —CONR—, NRCO—, —NRCO₂—,—SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—,—SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of R^(X)is independently selected from —R′, ═O, ═NR′, halogen, —NO₂, —CN, —OR′,—SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′,—CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′,—NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂,—OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂;

each occurrence of R^(5a) is independently an optionally substitutedC₁-C₆aliphatic group, halogen, —OR′, —SR′, —N(R′)₂, —NR′COR′,—NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂,—SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′,—COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂,or —OPO(R′)₂; and

each occurrence of R is independently hydrogen or an optionallysubstituted C₁₋₆ aliphatic group; and each occurrence of R′ isindependently hydrogen or an optionally substituted C₁₋₆ aliphaticgroup, a 3-8-membered saturated, partially unsaturated, or fullyunsaturated monocyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an 8-12 memberedsaturated, partially unsaturated, or fully unsaturated bicyclic ringsystem having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrencesof R′, are taken together with the atom(s) to which they are bound toform an optionally substituted 3-12 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, for compounds described directly above:

a) when R³ is at the 7-position of the quinazoline ring then:

-   -   i) when R³ is Cl or Me, ring A is unsubstituted naphthyl, and R¹        is hydrogen, then R² is not —(CH₂)₃NMe₂;    -   ii) when R³ is Cl, the sum of q and y is 1 and the phenyl ring        is substituted at the 4-position with Br, and R¹ is hydrogen,        then R² is not Cy¹, wherein Cy¹ is bonded to the nitrogen atom        through an optionally substituted C₁₋₄aliphatic group, wherein        one or more methylene units in the C₁₋₄aliphatic group are        optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—,        —SO₂NR—, or —NRSO₂—;    -   iii) when R³ is Cl or OMe, the sum of q and y is 1 and the        phenyl ring is substituted at the 4-position with either OMe or        Cl, and R¹ is hydrogen, then R² is not —CH(CH₃)(CH₂)₃N(Et)₂;    -   iv) when R³ is Me, OMe, or NO², and q and y are 0, then R¹ and        R² are not both methyl;    -   v) when R³ is OMe, q and y are 0, and R¹ is hydrogen, then R² is        not —SO₂(4-Me-phenyl);    -   vi) when R³ is F, the sum of q and y is 1 and the phenyl ring is        substituted at the 2-position with Cl, and R¹ is hydrogen, then        R² is not —(CH₂)morpholino; and

b) a) when R³ is at the 6-position of the quinazoline ring then:

-   -   i) when R³ is NH₂, Me, Cl, Br, —NHAc, the sum of q and y is 1        and the phenyl ring is substituted at the 4-position with F, or        ring A is naphthyl, and R¹ is hydrogen, then R² is not        —(CH₃)₃₋₄N(R′)₂;    -   ii) when R³ is —OCH₂Ph, or OH, and q and y are 0, then when R¹        is hydrogen, R² is not Me, nBu, or —(CH₂)₂-morpholino, or R¹ and        R² are not simultaneously Me or Et;    -   iii) when R³ is Me or Cl, and the sum of q and y are 1, then the        phenyl ring is not substituted in the 4-position with Br;    -   iv) when R³ is Cl, q and y are 0, and R¹ is hydrogen, then R² is        not —SO₂(4-Me-phenyl);    -   v) when R³ is OMe, and q and y are 0, and R¹ is hydrogen, then        R² is not —CH₂CH₂OH or —CH₂CH₂pyrrolidinyl;    -   vi) when R³ is Cl or Br, the sum of q and y is 1, and the phenyl        ring is substituted in the 4-position with —CH₂PO(OR′)₂, then R¹        is not hydrogen when R² is -Me, or R¹ and R² are not        simultaneously Me or Et;    -   vii) when R³ is OH and q and y are 0, then R¹ and R² are not        simultaneously —CH₂CH₂OMe;    -   viii) when R³ is Cl, the sum of q and y is 1 and the phenyl ring        is substituted in the 2-position with OnPr, and R¹ is hydrogen,        then R² is not —CH₂(1,3-benzodioxol);    -   ix) when R³ is OMe, OH, Br, C₁, NO₂, Me, and q and y are 0, then        when R¹ is hydrogen, R² is not Me, —CH₂CH₂COOMe, —CH₂COOMe, or        —(CH₂)₃CH₃, or R¹ and R² are not simultaneously Me; and    -   x) when R³ is Cl, the sum of q and y is 1 and the phenyl ring is        substituted in the 4-position with Cl, then R¹ and R² are not        simultaneously Me or iPr.

In certain other embodiments, for compounds described directly above:

a) one of R¹ or R² is hydrogen, and the other of R¹ and R² is selectedfrom:

-   -   i) Cy¹ wherein Cy¹ is bonded directly to the nitrogen atom or is        bonded through an optionally substituted C₁₋₄aliphatic group,        wherein one or more methylene units in the C₁₋₄aliphatic group        are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—,        —CONR—, —SO₂NR—, or —NRSO₂—; or    -   ii) an optionally substituted C₁₋₄ aliphatic group, wherein one        or more methylene units in the C₁₋₄aliphatic group are        optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—,        —SO₂NR—, or —NRSO₂—; or

b) R¹ and R² are each independently selected from Cy¹, wherein Cy¹ isbonded directly to the nitrogen atom or is bonded through an optionallysubstituted C₁₋₄aliphatic group, wherein one or more methylene units inthe C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or an optionally substitutedC₁₋₄aliphatic group, wherein one or more methylene units in theC₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO—,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—.

In still other embodiments, Cy¹ is:

In yet other embodiments, R¹ is hydrogen or an optionally substitutedC₁-C₄aliphatic group and R² is —CHR-Cy¹, wherein R is hydrogen orC₁-C₄alkyl, and Cy¹ is:

In yet other embodiments, R¹ and R² groups are each independently anoptionally substituted C₁₋₄aliphatic group and are each independentlyselected from optionally substituted methyl, ethyl, cyclopropyl,n-propyl, propenyl, cyclobutyl, (CO)OCH₂CH₃, (CH₂)₂OCH₃, CH₂CO)OCH₂CH₃,CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, or n-butyl.

In still other embodiments, for compounds described directly above, z is0-5, and R⁴ groups, when present, are each independently halogen, CN,NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′,—CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or anoptionally substituted group selected from C₁₋C₆aliphatic, aryl,heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl

In yet other embodiments, z is 0-5 and R⁴ groups are each independentlyCl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂,—O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂,—SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂,—C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃,—C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted groupselected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl,phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or—CH₂thiazolyl.

In still other embodiments, for compounds described directly above, R³is halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′,—COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′,—SO₂N(R′)₂, or an optionally substituted group selected fromC₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic,arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.

In yet other embodiments, R³ is Cl, Br, F, CF₃, —OCF₃, Me, Et, CN,—COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃,—OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂,—CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substitutedgroup selected from -piperidinyl, piperizinyl, morpholino, phenyl,phenyloxy, benzyl, or benzyloxy.

In still other embodiments, R³ is halogen, CN, optionally substitutedC₁-C₆alkyl, OR′, N(R′)₂, CON(R′)₂, or NRCOR′. In yet other embodiments,R³ is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In still otherembodiments, R³ is at the 6-position of the quinazoline ring and is —Cl,—CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In yet otherembodiments, R³ is at the 7-position of the quinazoline ring and is —Cl,—CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In still otherembodiments, R³ is at the 6-position of the quinazoline ring and is —Cl,—CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In yet otherembodiments, R³ is at the 7-position of the quinazoline ring and is —Cl,—CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In still otherembodiments, R³ is at the 6-position of the quinazoline ring and is—CON(R′)₂, or NRCOR′. In still other embodiments, R³ is at the7-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′.

In still other embodiments for compounds described directly above, y is0-5, q is 0-2, and R⁵ and R^(5a) groups, when present, are eachindependently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′,—SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂, —S(O)₂N(R′)₂, —OCOR′, —COR′, —CO₂R′,—OCON(R′)₂, —NR′SO₂R′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′,—PO(R′)₂, —OPO(R′)₂, or an optionally substituted group selected fromC₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic,arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.

In yet other embodiments, y is 0-5, and q is 1 or 2, and each occurrenceof R^(5a) is independently Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂,—N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃,—OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃,—OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂,OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionallysubstituted benzyloxy.

In still other embodiments, y is 0, and R^(5a) is F. In yet otherembodiments y is 0, q is 1, and R^(5a) is OR′. In still otherembodiments, y is 0, q is 1 and R^(5a) is OH. In yet other embodiments,y is 1, R^(5a) is OR′ and R⁵ is F, wherein OR′ is substituted at the2-position of the phenyl ring and F is substituted at the 6-position ofthe phenyl ring. In yet other embodiments, y is 1, R^(5a) is OH and R⁵is F, wherein OH is substituted at the 2-position of the phenyl ring andF is substituted at the 6-position of the phenyl ring.

In still other embodiments, R³ is substituted at the 6-position of thequinazoline ring, q is 1, and y is 0, and compounds have formula III:

In certain embodiments, for compounds described above,

a) R¹ and R² are each independently an optionally substituted groupselected from C₁₋₆aliphatic, Cy¹, wherein Cy¹ is a 5-7-memberedmonocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, oris a 3-12-membered saturated or partially unsaturated monocyclic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, wherein Cy¹ is bonded directly to the nitrogen atom or is bondedthrough an optionally substituted C₁₋₄aliphatic group, wherein one ormore methylene units in the C₁₋₄aliphatic group are optionally replacedwith —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—;wherein R¹ and R², are each optionally and independently substituted atone or more substitutable carbon, nitrogen, or sulfur atoms with zindependent occurrences of —R⁴, wherein z is 0-5;

b) z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃,—CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂,—COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂,—SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂,—NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, oran optionally substituted group selected from -piperidinyl, piperizinyl,morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy,—CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl;

c) R³ is Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂,—N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃,—CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃,—CONHCH₂CH₃, or an optionally substituted group selected from-piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, orbenzyloxy; and

d) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —SO₂NH₂,—SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂,4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or —COCH₃.

In certain other embodiments, for compounds described directly above R³is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In still otherembodiments, R³ is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or—OCH₂CH₃. In yet other embodiments, R³ is —CON(R′)₂, or NRCOR′. In stillother embodiments, R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃.

In still other embodiments, y is 0, and R^(5a) is F. In yet otherembodiments, y is 0, q is 1, and R^(5a) is OR′. In still otherembodiments, y is 0, q is 1 and R^(5a) is OH.

In certain other embodiments, for compounds described directly above:

a) Cy¹ is:

or R¹ and R² are each independently an optionally substitutedC₁₋₄aliphatic group and are each independently selected from optionallysubstituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl,(CO)OCH₂CH₃, (CH₂)₂OCH₃, CH₂CO)OCH₂CH₃, CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, orn-butyl;

b) z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃,—CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂,—COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂,—SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂,—NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, oran optionally substituted group selected from -piperidinyl, piperizinyl,morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy,—CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl;

c) R³ is Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂,—N(Et)₂, —N(iPr)O₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃,—CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃,—CONHCH₂CH₃, or an optionally substituted group selected from-piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, orbenzyloxy; and

d) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —SO₂NH₂,—SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂,4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or —COCH₃.

In certain embodiments, for compounds described directly above R³ is—Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —OCH₂CH₃, or —CN. In other embodiments, R³ is—Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In still otherembodiments, R³ is —CON(R′)₂, or NRCOR′. In yet other embodiments,R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃. In still otherembodiments, y is 0, and R^(5a) is F. In yet other embodiments y is 0, qis 1, and R^(5a) is OR′. In still other embodiments, y is 0, q is 1 andR^(5a) is OH.

In yet other embodiments, R³ is substituted at the 7-position of thequinazoline ring, q is 1, and y is 0, and compounds have formula IV:

a) wherein R¹ and R² are each independently an optionally substitutedgroup selected from C₁₋₆aliphatic, Cy¹, wherein Cy¹ is a 5-7-memberedmonocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, oris a 3-12-membered saturated or partially unsaturated monocyclic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, wherein Cy¹ is bonded directly to the nitrogen atom or is bondedthrough an optionally substituted C₁₋₄aliphatic group, wherein one ormore methylene units in the C₁₋₄aliphatic group are optionally replacedwith —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—;wherein R¹ and R², are each optionally and independently substituted atone or more substitutable carbon, nitrogen, or sulfur atoms with zindependent occurrences of —R⁴, wherein z is 0-5;

b) z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃,—CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂,—COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂,—SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂,—NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, oran optionally substituted group selected from -piperidinyl, piperizinyl,morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy,—CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl;

c) R³ is Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂,—N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃,—CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃,—CONHCH₂CH₃, or an optionally substituted group selected from-piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, orbenzyloxy; and

d) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —SO₂NH₂,—SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂,4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or —COCH₃.

In certain embodiments, for compounds described directly above, R³ is—Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In other embodiments,R³ is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In stillother embodiments, R³ is —CON(R′)₂, or NRCOR′. In yet other embodiments,R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃. In still otherembodiments, y is 0, and R^(5a) is F. In yet other embodiments y is 0, qis 1, and R^(5a) is OR′. In still other embodiments, y is 0, q is 1 andR^(5a) is OH.

In certain other embodiments, for compounds described directly above:

a) Cy¹ is:

or R¹ and R² are each independently an optionally substitutedC₁₋₄aliphatic group and are each independently selected from optionallysubstituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl,(CO)OCH₂CH₃, (CH₂)₂OCH₃, CH₂CO)OCH₂CH₃, CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, orn-butyl;

b) z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃,—CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂,—COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂,—SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂,—NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, oran optionally substituted group selected from -piperidinyl, piperizinyl,morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy,—CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl;

c) R³ is Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂,—N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃,—CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃,—CONHCH₂CH₃, or an optionally substituted group selected from-piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, orbenzyloxy; and

d) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —SO₂NH₂,—SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂,4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or —COCH₃.

In certain other embodiments, for compounds described directly above R³is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In other embodiments,R³ is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In stillother embodiments, R³ is —CON(R′)₂, or NRCOR′. In yet other embodiments,R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, or —OCH₂CH₃. In still otherembodiments, y is 0, and R^(5a) is F. In yet other embodiments y is 0, qis 1, and R^(5a) is OR′. In still other embodiments, y is 0, q is 1 andR^(5a) is OH.

For compounds described in this section above, in general, compounds areuseful as inhibitors of ion channels, preferably voltage gated sodiumchannels and N-type calcium channels. In certain exemplary embodiments,compounds of the invention are useful as inhibitors of NaV1.8. In otherembodiments, compounds of the invention are useful as inhibitors ofNaV1.8 and CaV2.2. In still other embodiments, compounds of theinvention are useful as inhibitors of CaV2.2. In yet other embodiments,compounds of the invention are useful as dual inhibitors of NaV1.8 and aTTX-sensitive ion channel such as NaV1.3 or NaV1.7.

IV. Compounds of Formula V

wherein R¹ and R² are each independently an optionally substituted groupselected from C₁₋₆aliphatic, Cy¹, wherein Cy¹ is a 5-7-memberedmonocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, oris a 3-12-membered saturated or partially unsaturated monocyclic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, wherein Cy¹ is bonded directly to the nitrogen atom or is bondedthrough an optionally substituted C₁₋₄aliphatic group, wherein one ormore methylene units in the C₁₋₄aliphatic group are optionally replacedwith —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or R¹and R², taken together with the nitrogen atom to which they are bound,form an optionally substituted 3-12-membered monocyclic or bicyclicsaturated or partially unsaturated ring having 0-3 additionalheteroatoms independently selected from nitrogen, sulfur, or oxygen;wherein R¹ and R², or the ring formed by R¹ and R² taken together, areeach optionally and independently substituted at one or moresubstitutable carbon, nitrogen, or sulfur atoms with z independentoccurrences of —R⁴, wherein z is 0-5;

x is 0-4;

y is 0-2;

each occurrence of R³, R⁴, and R⁵ is independently Q-R^(X); wherein Q isa bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacentmethylene units of Q are optionally and independently replaced by —NR—,—S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—,—SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—,—SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of R^(X)is independently selected from —R′, ═O, ═NR′, halogen, —NO₂, —CN, —OR′,—SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′,—CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′,—NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂,—OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂;

R^(5a) is an optionally substituted C₁-C₆aliphatic group, halogen, —OR′,—SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′,—CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′,—NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂,—OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂; and

each occurrence of R is independently hydrogen or an optionallysubstituted C₁₋₆ aliphatic group; and each occurrence of R isindependently hydrogen or an optionally substituted C₁₋₆ aliphaticgroup, a 3-8-membered saturated, partially unsaturated, or fullyunsaturated monocyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an 8-12 memberedsaturated, partially unsaturated, or fully unsaturated bicyclic ringsystem having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrencesof R′, are taken together with the atom(s) to which they are bound toform an optionally substituted 3-12 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, for compounds described directly above, when xis 1 and R³ is 6-OMe, R¹ is hydrogen, and y and q are both 0, then R² isnot —CH₂CH₂OCH₂CH₂OH or the monomethanesulfonate salt.

In certain other embodiments, for compounds described directly above,

a) one of R¹ or R² is hydrogen, and the other of R¹ and R² is selectedfrom:

-   -   i) Cy¹ wherein Cy¹ is bonded directly to the nitrogen atom or is        bonded through an optionally substituted C₁₋₄aliphatic group,        wherein one or more methylene units in the C₁₋₄aliphatic group        are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—,        CONR—, —SO₂NR—, or —NRSO₂—; or    -   ii) an optionally substituted C₁₋₄aliphatic group, wherein one        or more methylene units in the C₁₋₄aliphatic group are        optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—,        —SO₂NR—, or —NRSO₂—; or

b) R¹ and R² are each independently selected from Cy¹, wherein Cy¹ isbonded directly to the nitrogen atom or is bonded through an optionallysubstituted C₁₋₄aliphatic group, wherein one or more methylene units inthe C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or an optionally substitutedC₁₋₄aliphatic group, wherein one or more methylene units in theC₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO—,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—.

In other embodiments, Cy¹ is:

In still other embodiments, R¹ is hydrogen or an optionally substitutedC₁-C₄aliphatic group and R² is —CHR-Cy¹, wherein R is hydrogen orC₁-C₄alkyl, and Cy¹ is:

In still other embodiments, R¹ and R² groups are each independently anoptionally substituted C₁₋₄aliphatic group and are each independentlyselected from optionally substituted methyl, ethyl, cyclopropyl,n-propyl, propenyl, cyclobutyl, (CO)OCH₂CH₃, (CH₂)₂OCH₃, CH₂CO)OCH₂CH₃,CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, or n-butyl.

In yet other embodiments for compounds described directly above, R¹ andR², taken together with the nitrogen atom to which they are bound, forman optionally substituted 3-12 membered heterocyclyl ring having 1-3heteroatoms independently selected from nitrogen or oxygen and form a3-12 membered heterocyclyl group selected from:

wherein the ring formed by R¹ and R² taken together, is optionallysubstituted at one or more substitutable carbon, nitrogen, or sulfuratoms with z independent occurrences of —R⁴, and z is 0-5.

In other embodiments, for compounds of formula I-A, R¹ and R² takentogether are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl(ff), piperidin 1-yl (dd), piperazin-1-yl (cc), or morpholin-4-yl (ee).In other embodiments, for compounds of formula I-A, R¹ and R² takentogether are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl(ff), piperidin1-yl (dd), or piperazin-1-yl (cc). In yet otherembodiments, for compounds of formula I-A, R¹ and R², taken together isoptionally substituted azetidin-1-yl (jj). In yet other embodiments, forcompounds of formula I-A, R¹ and R², taken together is optionallysubstituted pyrrolidin-1-yl (ff). In still other embodiments, forcompounds of formula I-A, R¹ and R², taken together is optionallysubstituted piperidin1-yl (dd). In yet other embodiments, for compoundsof formula I-A, R¹ and R², taken together is optionally substitutedpiperazin-1-yl (cc).

In still other embodiments, for compounds described directly above, z is0-5, and R⁴ groups, when present, are each independently halogen, CN,NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′,—CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or anoptionally substituted group selected from C₁₋C₆aliphatic, aryl,heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.

In yet other embodiments, z is 0-5 and R⁴ groups are each independentlyCl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂,—O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂,—SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂,—C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃,—C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted groupselected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl,phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or—CH₂thiazolyl.

In certain embodiments, for compounds of formula I-A, R¹ and R², takentogether is optionally substituted azetidin-1-yl (jj), wherein z is 1 or2 and at least one occurrence of R⁴ is —NRSO₂R′, —NRCOOR′, or —NRCOR′.In certain other embodiments, for compounds of formula I-A, R¹ and R²,taken together is optionally substituted azetidin-1-yl (jj), wherein zis 1 and R⁴ is —NRSO₂R′. In other embodiments, for compounds of formulaI-A, R¹ and R², taken together is optionally substituted azetidin-1-yl(jj), wherein z is 1 and R⁴ is —NRCOOR′. In certain other embodiments,for compounds of formula I-A, R¹ and R², taken together is optionallysubstituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRCOR′. In yetother embodiments, for compounds of formula I-A, R¹ and R², takentogether is optionally substituted pyrrolidin-1-yl (ff), wherein z is 1or 2 and R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In stillother embodiments, for compounds of formula I-A, R¹ and R², takentogether is optionally substituted piperidin-1-yl (dd), wherein z is 1or 2 and at least one occurrence of R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃,—OR′, or —CH₂OR′, —NRSO₂R′, —NRCOOR′, or —OCON(R′)₂. In certain otherembodiments, for compounds of formula I-A, R¹ and R², taken together isoptionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is F,CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In other embodiments, for compoundsof formula I-A, R¹ and R², taken together is optionally substitutedpiperidin-1-yl (dd), wherein z is 1 and R⁴ is —NRSO₂R′. In certain otherembodiments, for compounds of formula I-A, R¹ and R², taken together isoptionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is—NRCOOR′. In yet other embodiments, for compounds of formula I-A, R¹ andR², taken together is optionally substituted piperazin-1-yl (cc),wherein z is 1 or 2 and at least one occurrence of R⁴ is —SOR′,—CON(R′)₂, —SO₂N(R′)₂, —COR′, or —COOR′. In certain other embodiments,for compounds of formula I-A, R¹ and R², taken together is optionallysubstituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —SOR′. Incertain other embodiments, for compounds of formula I-A, R¹ and R²,taken together is optionally substituted piperazin-1-yl (cc), wherein zis 1 and R⁴ is —COOR′. In certain other embodiments, for compounds offormula I-A, R¹ and R², taken together is optionally substitutedpiperazin-1-yl (cc), wherein z is 1 and R⁴ is —CON(R′)₂. In certainother embodiments, for compounds of formula I-A, R¹ and R², takentogether is optionally substituted piperazin-1-yl (cc), wherein z is 1and R⁴ is —SO₂N(R′)₂. In certain other embodiments, for compounds offormula I-A, R¹ and R², taken together is optionally substitutedpiperazin-1-yl (cc), wherein z is 1 and R⁴ is —COR′.

In still other embodiments, x is 0-4, and R³ groups, when present, areeach independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′,—SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′,—SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected fromC₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic,arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl. In yet other embodiments, x is 1 or 2,and each occurrence of R³ is independently Cl, Br, F, CF₃, —OCF₃, Me,Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂,—COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂,—CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substitutedgroup selected from -piperidinyl, piperizinyl, morpholino, phenyl,phenyloxy, benzyl, or benzyloxy.

In still other embodiments, x is 1 or 2 and each R³ group isindependently halogen, CN, optionally substituted C₁-C₆alkyl, OR′,N(R′)₂, CON(R′)₂, or NRCOR′. In yet other embodiments, x is 1 or 2, andeach R³ group is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃,—CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In stillother embodiments, x is 1 and R³ is at the 6-position of the quinazolinering and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In yet otherembodiments, x is 1 and R³ is at the 7-position of the quinazoline ringand is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In still otherembodiments, x is 1 and R³ is at the 6-position of the quinazoline ringand is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In yetother embodiments, x is 1 and R³ is at the 7-position of the quinazolinering and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. Instill other embodiments, x is 1 and R³ is at the 6-position of thequinazoline ring and is —CON(R′)₂, or NRCOR′. In yet other embodiments,x is 1 and R³ is at the 7-position of the quinazoline ring and is—CON(R′)₂, or NRCOR′.

In still other embodiments for compounds described directly above, y is0-2, q is 0-2, and R⁵ and R^(5a) groups, when present, are eachindependently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′,—SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂, —S(O)₂N(R′)₂, —OCOR′, —COR′, —CO₂R′,—OCON(R′)₂, —NR′SO₂R′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′,—PO(R′)₂, —OPO(R′)₂, or an optionally substituted group selected fromC₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic,arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.

In yet other embodiments, y is 0-2, and q is 1 or 2, and each occurrenceof R^(5a) is independently Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂,—N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃,—OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃,—OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂,OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionallysubstituted benzyloxy.

In still other embodiments, y is 0, and q is 1 and R^(5a) is F. In yetother embodiments, y is 0, q is 1, and R^(5a) is OR′. In still otherembodiments, y is 0, q is 1 and R^(5a) is OH. In yet other embodiments,y is 0, q is 2 and one occurrence of R^(5a) is OR′ and the otheroccurrence of R^(5a) is F. In yet other embodiments, y is 0, q is 2 andone occurrence of R^(5a) is OH and the other occurrence of R^(5a) is F.

In still other embodiments:

a) R¹ and R² taken together is an optionally substituted ring selectedfrom azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidin1-yl (dd), orpiperazin-1-yl (cc); one of R¹ or R² is hydrogen, and the other of R¹and R² is selected from Cy¹, wherein Cy¹ is bonded directly to thenitrogen atom or is bonded through an optionally substitutedC₁₋₄aliphatic group, wherein one or more methylene units in theC₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—,—NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—, or an optionally substitutedC₁₋₄aliphatic group, wherein one or more methylene units in theC₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—,—NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or R¹ and R² are each independentlyselected from an optionally substituted C₁₋₄aliphatic group, wherein oneor more methylene units in the C₁₋₄aliphatic group are optionallyreplaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or—NRSO₂—; or Cy¹ wherein Cy¹ is bonded to the nitrogen atom directly oris bonded through an optionally substituted C₁₋₄aliphatic group, whereinone or more methylene units in the C₁₋₄aliphatic group are optionallyreplaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or—NRSO₂—;

b) z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃,—CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂,—COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂,—SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂,—NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, oran optionally substituted group selected from -piperidinyl, piperizinyl,morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy,—CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl;

c) x is 0, 1, or 2, and each occurrence of R³ is independently Cl, Br,F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂,—O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃,—NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or anoptionally substituted group selected from -piperidinyl, piperizinyl,morpholino, phenyl, phenyloxy, benzyl, or benzyloxy;

d) wherein y is 0-2, and R⁵ groups, when present, are each independentlyCl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂,—O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃,—SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂,4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), —COCH₃, optionallysubstituted phenoxy, or optionally substituted benzyloxy; and

e) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —SO₂NH₂,—SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂,4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or —COCH₃.

In yet other embodiments, for compounds of formula I-A, R¹ and R², takentogether is optionally substituted azetidin-1-yl (jj). In yet otherembodiments, for compounds of formula I-A, R¹ and R², taken together isoptionally substituted pyrrolidin-1-yl (ff). In still other embodiments,for compounds of formula I-A, R¹ and R², taken together is optionallysubstituted piperidin1-yl (dd). In yet other embodiments, for compoundsof formula I-A, R¹ and R², taken together is optionally substitutedpiperazin-1-yl (cc).

In certain embodiments, for compounds of formula I-A, R¹ and R², takentogether is optionally substituted azetidin-1-yl (jj), wherein z is 1 or2 and at least one occurrence of R⁴ is —NRSO₂R′, —NRCOOR′, or —NRCOR′.In certain other embodiments, for compounds of formula I-A, R¹ and R²,taken together is optionally substituted azetidin-1-yl (jj), wherein zis 1 and R⁴ is —NRSO₂R′. In other embodiments, for compounds of formulaI-A, R¹ and R², taken together is optionally substituted azetidin-1-yl(jj), wherein z is 1 and R⁴ is —NRCOOR′. In certain other embodiments,for compounds of formula I-A, R¹ and R², taken together is optionallysubstituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRCOR′. In yetother embodiments, for compounds of formula I-A, R¹ and R², takentogether is optionally substituted pyrrolidin-1-yl (ft), wherein z is 1or 2 and R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In stillother embodiments, for compounds of formula I-A, R¹ and R², takentogether is optionally substituted piperidin-1-yl (dd), wherein z is 1or 2 and at least one occurrence of R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃,—OR′, or —CH₂OR′, —NRSO₂R′, —NRCOOR′, or —OCON(R′)₂. In certain otherembodiments, for compounds of formula I-A, R¹ and R², taken together isoptionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is F,CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In other embodiments, for compoundsof formula I-A, R¹ and R², taken together is optionally substitutedpiperidin-1-yl (dd), wherein z is 1 and R⁴ is —NRSO₂R′. In certain otherembodiments, for compounds of formula I-A, R¹ and R², taken together isoptionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is—NRCOOR′. In yet other embodiments, for compounds of formula I-A, R¹ andR², taken together is optionally substituted piperazin-1-yl (cc),wherein z is 1 or 2 and at least one occurrence of R⁴ is —SOR′,—CON(R′)₂, —SO₂N(R′)₂, —COR′, or —COOR′. In certain other embodiments,for compounds of formula I-A, R¹ and R², taken together is optionallysubstituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —SOR′. Incertain other embodiments, for compounds of formula I-A, R¹ and R²,taken together is optionally substituted piperazin-1-yl (cc), wherein zis 1 and R⁴ is —COOR′. In certain other embodiments, for compounds offormula I-A, R¹ and R², taken together is optionally substitutedpiperazin-1-yl (cc), wherein z is 1 and R⁴ is —CON(R′)₂. In certainother embodiments, for compounds of formula I-A, R¹ and R², takentogether is optionally substituted piperazin-1-yl (cc), wherein z is 1and R⁴ is —SO₂N(R′)₂. In certain other embodiments, for compounds offormula I-A, R¹ and R², taken together is optionally substitutedpiperazin-1-yl (cc), wherein z is 1 and R⁴ is —COR′.

In yet other embodiments for compounds described directly above, x is 1and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃,—CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl),—OCH₃, —NH₂, —OCH₂CH₃, or —CN. In still other embodiments, x is 1 and R³is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃,—F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂,—OCH₂CH₃, or —CN. In yet other embodiments, x is 1 and R³ is at the6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —OCH₃, or —OCH₂CH₃. In still other embodiments, x is 1 and R³ isat the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F,—CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In yet other embodiments, x is 1 and R³is at the 6-position of the quinazoline ring and is —CON(R′)₂, orNRCOR′. In yet other embodiments, x is 1 and R³ is at the 7-position ofthe quinazoline ring and is —CON(R′)₂, or NRCOR′. In yet otherembodiments, R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃. Instill other embodiments, y is 0, and q is 1 and R^(5a) is F. In yetother embodiments, y is 0, q is 1, and R^(5a) is OR′. In still otherembodiments, y is 0, q is 1 and R^(5a) is OH. In yet other embodiments,y is 0, q is 2 and one occurrence of R^(5a) is OR′ and the otheroccurrence of R^(5a) is F. In yet other embodiments, y is 0, q is 2 andone occurrence of R^(5a) is OH and the other occurrence of R^(5a) is F.

In certain embodiments, for compounds described directly above,

a) Cy¹ is:

or R¹ and R² are each independently an optionally substitutedC₁₋₄aliphatic group and are each independently selected from optionallysubstituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl,(CO)OCH₂CH₃, (CH₂)₂OCH₃, CH₂CO)OCH₂CH₃, CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, orn-butyl;

b) z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃,—CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂,—COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂,—SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂,—NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, oran optionally substituted group selected from -piperidinyl, piperizinyl,morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy,—CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl;

c) x is 0, 1, or 2, and each occurrence of R³ is independently Cl, Br,F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂,—O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃,—NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or anoptionally substituted group selected from -piperidinyl, piperizinyl,morpholino, phenyl, phenyloxy, benzyl, or benzyloxy;

d) wherein y is 0-5, and R⁵ groups, when present, are each independentlyCl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂,—O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃,—SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂,4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), —COCH₃, optionallysubstituted phenoxy, or optionally substituted benzyloxy; and

e) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —SO₂NH₂,—SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂,4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or —COCH₃.

In yet other embodiments for compounds described directly above, x is 1and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃,—CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl),—OCH₃, —OCH₂CH₃, or —CN. In still other embodiments, x is 1 and R³ is atthe 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F,—CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂,—OCH₂CH₃, or —CN. In yet other embodiments, x is 1 and R³ is at the6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —OCH₃, or —OCH₂CH₃. In still other embodiments, x is 1 and R³ isat the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F,—CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In yet other embodiments, x is 1 and R³is at the 6-position of the quinazoline ring and is —CON(R′)₂, orNRCOR′. In yet other embodiments, x is 1 and R³ is at the 7-position ofthe quinazoline ring and is —CON(R′)₂, or NRCOR′. In yet otherembodiments, R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃. Instill other embodiments, y is 0, and q is 1 and R^(5a) is F. In yetother embodiments, y is 0, q is 1, and R^(5a) is OR′. In still otherembodiments, y is 0, q is 1 and R^(5a) is OH. In yet other embodiments,y is 0, q is 2 and one occurrence of R^(5a) is OR′ and the otheroccurrence of R^(5a) is F. In yet other embodiments, y is 0, q is 2 andone occurrence of R^(5a) is OH and the other occurrence of R^(5a) is F.

For compounds described in this section above, in general, compounds areuseful as inhibitors of ion channels, preferably voltage gated sodiumchannels and N-type calcium channels. In certain exemplary embodiments,compounds of the invention are useful as inhibitors of NaV1.8. In otherembodiments, compounds of the invention are useful as inhibitors ofNaV1.8 and CaV2.2. In still other embodiments, compounds of theinvention are useful as inhibitors of CaV2.2. In yet other embodiments,compounds of the invention are useful as dual inhibitors of NaV1.8 and aTTX-sensitive ion channel such as NaV1.3 or NaV1.7.

V. Compounds of Formula I-B-i

or a pharmaceutically acceptable salt thereof,

wherein R¹ is selected from C₁₋₆aliphatic, Cy¹, wherein Cy¹ is a5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or is a 3-12-membered saturated or partially unsaturatedmonocyclic ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, wherein Cy¹ is bonded directly to thenitrogen atom or is bonded through an optionally substitutedC₁₋₄aliphatic group, wherein one or more methylene units in theC₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—,—NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; wherein R¹ is optionallysubstituted at one or more substitutable carbon, nitrogen, or sulfuratoms with z independent occurrences of —R⁴, wherein z is 0-5;

x is 0-4;

y is 0-4;

each occurrence of R³, R⁴, and R⁵ is independently Q-R^(X); wherein Q isa bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacentmethylene units of Q are optionally and independently replaced by —NR—,—S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—,—SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—,—SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of R^(X)is independently selected from —R′, ═O, ═NR′, halogen, —NO₂, —CN, —OR′,—SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′,—CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′,—NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂,—OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂;

each occurrence of R^(5a) is independently an optionally substitutedC₁-C₆aliphatic group, halogen, —OR′, —SR′, —N(R′)₂, —NR′COR′,—NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂,—SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′,—COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂,or —OPO(R′)₂; and

each occurrence of R is independently hydrogen or an optionallysubstituted C₁₋₆ aliphatic group; and each occurrence of R′ isindependently hydrogen or an optionally substituted C₁₋₆ aliphaticgroup, a 3-8-membered saturated, partially unsaturated, or fullyunsaturated monocyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an 8-12 memberedsaturated, partially unsaturated, or fully unsaturated bicyclic ringsystem having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrencesof R′, are taken together with the atom(s) to which they are bound toform an optionally substituted 3-12 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

For compounds described directly above, in certain embodiments,

a) when R^(5a) is Me, Cl, or OMe, and x is 0, then R¹ is not Et or Me;

b) when R^(5a) is Cl, x is 3, and the three occurrences of R³ are 6-Me,7-COOEt, and 8-Me, then R¹ is not —(CH₂)₂piperidin-1-yl;

c) when R^(5a) is Me, x is 1 and R³ is NO₂ or NH₂, then R¹ is not Et;

d) when R^(5a) is OH, NHMe, or N(NO)Me, and x is 0, then R¹ is not Et,Me or —CH₂CH═CH₂;

e) when R^(5a) is NH², and x is 0, then R¹ is not —COCH₃;

f) when R^(5a) is Cl or Me, and y is 0 or 1 and when y is 1, R⁵ is 4-Cl,and x is 0, then R¹ is not 4-CN-phenyl, 4-Me-phenyl, 4-OMe-phenyl,4-Cl-phenyl, 4-NO₂-phenyl, —CH₂CH₂NHMe, Et, Me, 4-COOMe-phenyl, —CH₂Ph,iPr, 2-Me-phenyl, 4-phenyl-phenyl, or —CH₂CH═CH₂.

For compounds described directly above, in certain other embodiments,

a) R¹ is selected from:

-   -   i) Cy¹ wherein Cy¹ is bonded directly to the nitrogen atom or is        bonded through an optionally substituted C₁₋₄aliphatic group,        wherein one or more methylene units in the C₁₋₄aliphatic group        are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—,        —CONR—, —SO₂NR—, or —NRSO₂—; or    -   ii) an optionally substituted C₁₋₄aliphatic group, wherein one        or more methylene units in the C₁₋₄aliphatic group are        optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—,        —SO₂NR—, or —NRSO₂—.

For compounds described directly above, in certain embodiments Cy¹ is,

In other embodiments, R¹ is —CHR-Cy¹, wherein R is hydrogen orC₁-C₄alkyl, and Cy¹ is:

In still other embodiments, R¹ is an optionally substitutedC₁₋₄aliphatic group and are each independently selected from optionallysubstituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl,(CO)OCH₂CH₃, (CH₂)₂OCH₃, CH₂CO)OCH₂CH₃, CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, orn-butyl.

In yet other embodiments, z is 0-5, and R⁴ groups, when present, areeach independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′,—SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′,—SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected fromC₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic,arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.

In still other embodiments, z is 0-5 and R⁴ groups are eachindependently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂,—N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃,—SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃,—C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃,—COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionallysubstituted group selected from -piperidinyl, piperizinyl, morpholino,C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl,pyridyl, —CH₂pyridyl, or —CH₂thiazolyl.

In yet other embodiments, R³ is halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂,—OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂,COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted groupselected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic,heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl,cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.

In still other embodiments, R³ is Cl, Br, F, CF₃, —OCF₃, Me, Et, CN,—COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃,—OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂,—CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substitutedgroup selected from -piperidinyl, piperizinyl, morpholino, phenyl,phenyloxy, benzyl, or benzyloxy.

In yet other embodiments, R³ is halogen, CN, optionally substitutedC₁-C₆alkyl, OR′, N(R′)₂, CON(R′)₂, or NRCOR′. In still otherembodiments, R³ is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃,—CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In yetother embodiments, R³ is at the 6-position of the quinazoline ring andis —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In still otherembodiments, R³ is at the 7-position of the quinazoline ring and is —Cl,—CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In yet otherembodiments, R³ is at the 6-position of the quinazoline ring and is —Cl,—CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In still otherembodiments, R³ is at the 7-position of the quinazoline ring and is —Cl,—CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In otherembodiments, R³ is at the 6-position of the quinazoline ring and is—CON(R′)₂, or NRCOR′. In yet other embodiments, R³ is at the 7-positionof the quinazoline ring and is —CON(R′)₂, or NRCOR′.

In yet other embodiments, for compounds described directly above, y is0-5, q is 0-2, and R⁵ and R^(5a) groups, when present, are eachindependently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′,—SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂, —S(O)₂N(R′)₂, —OCOR′, —COR′, —CO₂R′,—OCON(R′)₂, —NR′SO₂R′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′,—PO(R′)₂, —OPO(R′)₂, or an optionally substituted group selected fromC₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic,arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.

In still other embodiments, y is 0-5, and q is 1 or 2, and eachoccurrence of R^(5a) is independently Cl, Br, F, CF₃, Me, Et, CN, —COOH,—NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH,—OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃,—OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂,OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionallysubstituted benzyloxy.

In still other embodiments, y is 0, and R^(5a) is F. In yet otherembodiments, y is 0, q is 1, and R^(5a) is OR′. In still otherembodiments, y is 0, q is 1 and R^(5a) is OH. In yet other embodiments,y is 1, R^(5a) is OR′ and R⁵ is F, wherein OR′ is substituted at the2-position of the phenyl ring and F is substituted at the 6-position ofthe phenyl ring. In yet other embodiments, y is 1, R^(5a) is OH and R⁵is F, wherein OH is substituted at the 2-position of the phenyl ring andF is substituted at the 6-position of the phenyl ring.

For compounds described in this section above, in general, compounds areuseful as inhibitors of ion channels, preferably voltage gated sodiumchannels and N-type calcium channels. In certain exemplary embodiments,compounds of the invention are useful as inhibitors of NaV1.8. In otherembodiments, compounds of the invention are useful as inhibitors ofNaV1.8 and CaV2.2. In still other embodiments, compounds of theinvention are useful as inhibitors of CaV2.2. In yet other embodiments,compounds of the invention are useful as dual inhibitors of NaV1.8 and aTTX-sensitive ion channel such as NaV1.3 or NaV1.7.

Representative examples of compounds as described above and herein areset forth below in Table 2.

Lengthy table referenced here US20110021495A1-20110127-T00001 Pleaserefer to the end of the specification for access instructions.

4. General Synthetic Methodology:

The compounds of this invention may be prepared in general by methodsknown to those skilled in the art for analogous compounds, asillustrated by the general scheme below, and the preparative examplesthat follow.

Scheme A below depicts general conditions for the synthesis of compoundsof formula IA where X is NR². In general, the useful intermediate iiican be obtained by condensing a benzoylchloride with an anthranilamide.

Reaction of i and ii (step a) using K₂CO₃ and ether under refluxconditions, and subsequent treatment with 5% aq. NaOH under refluxconditions yields intermediate iii. Reaction of intermediate iii withPOCl₃ to generate the 4-chloro compound, and subsequent reaction with i)N,N-dimethylaniline in benzene under reflux conditions; ii) BBr₃,CH₂Cl₂, −78° C.; and iii) R¹R²NH, in THF/CH₂Cl₂ at room temperatureyields the desired product IA.

Reaction of i and ii (step a) using triethylamine and 1,4-Dioxane underambient conditions yields intermediate iii. Reaction of intermediate iii(step b) with 0.5M solution of ammonia in 1,4-Dioxane, triethylamine andBOP reagent was stirred at ambient temperature for 16 h to yieldintermediate iv. Treatment of iv with 5% aq. NaOH under refluxconditions yields intermediate v. Treatment of v with POCl₃ to generatethe 4-chloro compound, and subsequent reaction with i)N,N-dimethylaniline in benzene under reflux conditions; ii) BBr₃,CH₂Cl₂, −78° C.; and iii) R¹R²NH, in THF/CH₂Cl₂ at room temperatureyields the desired product IA.

Reaction of i and ii (step a) using pyridine yields intermediate iii.Treatment of iii with 5% aq. NaOH under reflux conditions yieldsintermediate iv. Reaction of intermediate iv with POCl₃ to generate the4-chloro compound, and subsequent reaction with i) N,N-dimethylanilinein benzene under reflux conditions; ii) BBr₃, CH₂Cl₂, −78° C.; and iii)R¹R²NH, in THF/CH₂Cl₂ at room temperature yields the desired product IA.

Schemes D and E below depict the synthesis of a variety of usefulanthranilimides:

Reaction of i (step a) with chloral hydrate in the presence ofhydroxylamine hydrochloride yields isatin ii. Treatment of ii with basichydrogen peroxide gives iii (step b), useful as shown in Scheme D.

Reaction of i (step a) with Boc anhydride yields ii. Subsequentmetalation of ii with butyl lithium at low temperature and reaction withCO₂ yields the N-protected anthranilic acid (step b). Boc removal withTFA yields the anthranilic acid iii, useful as shown in Scheme E.

Reaction of isatoic anhydrides i (step a) with aqueous ammoniumhydroxide yields ii, useful as shown in Scheme F.

(step a) i) Treatment of i in water with AcOH and KOCN 0° C. to roomtemperature for 24 h, and subsequent reaction with ii) NaOH followed byacidification with HCl yields intermediate ii. (step b) Treatment of iiwith POCl₃ and triethylamine under reflux conditions yields intermediateiii. (step c) Treatment of iii with R¹R²NH, in THF/CH₂Cl₂ 0° C. to roomtemperature yields intermediate iv.

Reaction of intermediate i (step a) with POCl₃ generates the2,4-dichloro compound ii. Reaction of intermediate ii (step b) withR₁—NH—R₂, and Et₃N, in CH₂Cl₂ yields amine iii. Reaction of intermediateiii (step c) with an NH containing heterocycle, NaH, and THF generatesiv. Reaction of intermediate iii (step d) with LiHMDS, Pd₂(dba)₃,2-(dicyclohexyl)phosphinobiphenyl, and THF yields diamine v. Reaction ofintermediate v (step e) with a substituted 2,5-dimethoxytetrahydrofuran,in AcOH generates vi. Reaction of intermediate v (step withClCO—CH₂—(CH₂)_(n)—CH₂—Cl, Et₃N, and p-dioxane generates vii. Reactionof intermediate iii (step g) with a cyclic anhydride, and p-dioxanegenerates viii.

Reaction of intermediate i (step a) with POCl₃ and subsequent treatmentwith BBr₃, CH₂Cl₂, at −78° C. generates the 4-chloro compound ii.Reaction of intermediate ii (step b) with R′—NH—R²—X(R′″)H, and Et₃N, inCH₂Cl₂ yields iii. Reaction of intermediate iii (step c) withR′N(R″)X—SO₂Cl, and Et₃N, in CH₂Cl₂ generates iv. Reaction ofintermediate iii (step d) with R′—SO₂Cl, and Et₃N, in CH₂Cl₂ generatesv. Reaction of intermediate iii (step e) with R′—CO₂Cl, and Et₃N, inCH₂Cl₂ or with phosgene, and R′(R″)XH generates vi. Reaction ofintermediate iii (step f) with R′COCl, Et₃N, in CH₂Cl₂ generates vi.Reaction of intermediate iii (step g) with electrophiles in the presenceof Et₃N (organic halide electrophiles) or NaBH(OAc)₃ (aldehyde andketone electrophiles) yields viii.

Reaction of i with ii in dichloromethane under microwave irradiation at150° C. yields product iii.

Conditions: (a) for M=Li: s-BuLi, TMEDA, THF, −78° C.; for M=ZnX: i.s-BuLi, TMEDA, THF, −78° C.; ii. ZnCl₂; for M=MgX: Mg, THF, reflux. (b)i. RSSR; ii. H₂O₂ (n=1) or KMnO₄ (n=2). (c) R¹R²C═O, THF, −78° C. to RT.(d) CO₂, THF, −78° C. to RT. (e) for R¹═H: R²NCO; others: R¹R²COCl, THF.(f) i. H₂C═O; ii. PBr₃; iii. R¹R²NH. (g) Het-OTf, Ni(acac)₂, PPh₃,MeMgBr, THF, RT. (h) is B(OMe)₃; ii. ArX (X=halogen), Pd(PPh₃)₄, NaOEt,toluene, 80° C. (i) i. SOCl₂, CH₂Cl₂; ii. R¹Sn(R)₃, Pd(PPh₃)₄, toluene;iii. R¹MgX, THF. (j) i. SOCl₂, CH₂Cl₂; ii. R¹R²NH, THF. (k) LiAlH₄, THF.

Conditions: (a) For M=Li: s-BuLi, TMEDA, THF, −78° C.; for M=ZnX: i.s-BuLi, TMEDA, THF, −78° C.; ii. ZnCl₂; for M=MgX: Mg, THF, reflux. (b)i. RSSR; ii. H₂O₂ (n=1) or KMnO₄ (n=2). (c) R′R²C═O, THF, −78° C. to RT.(d) CO₂, THF, −78° C. to RT. (e) for R¹═H: R²NCO; others: R¹R²COCl, THF.(f) i. H₂C═O; ii. PBr₃; iii. R¹R²NH. (g) Het-OTf, Ni(acac)₂, PPh₃,MeMgBr, THF, RT. (h) for R¹=Aryl: i. B(OMe)₃; ii. ArX (X=halogen),Pd(PPh₃)₄, NaOEt, toluene, 80° C. for R¹=alkyl: R¹I, THF, −78° C. to RT.(i) i. SOCl₂, CH₂Cl₂; ii. R¹Sn(R)₃, Pd(PPh₃)₄, toluene; iii. R²MgX, THF.(j) i. SOCl₂, CH₂Cl₂; ii. R¹R²NH, THF. (k) LiAlH₄, THF. (l) ArXB(OR)₂,Pd(PPh₃)₄, NaOEt, toluene, 80° C.

Treatment of i with ii using palladium catalyzed conditions (step a)Pd(dppf)Cl₂, KOAc, in DMSO or DMF at 84° C. for 2-6 hours yieldsintermediate iii. Reaction of intermediate iii with intermediate ivusing palladium cross coupling conditions (step b) Pd(dppf)Cl2 or(Ph₃P)₄Pd, K₂CO₃, DMF:H₂O (4:1) under microwave irradiation at 170° C.for 6 minutes yields compound v.

Treatment of i with t-BuLi at −78° C., followed by addition of solid CO₂and warming to room temperature yield carboxylate ii. The carboxylate inii can be retained or utilized for reactions characteristic of thefunctional group.

Palladium catalyzed cross coupling of i with the appropriate amine intoluene (80° C.) yields ii.

Conditions: (a) R⁴COCl, pyridine, CH₂Cl₂, 0° C., then RT.

Reaction of i with iia or iib (step a), treatment with triethylamine inTHF/CH₂Cl₂ at room temperature yields compounds iii and v respectively.Treatment of iii (step b) with i) NaH in THF 0° C., then reaction withelectrophiles at 0° C. to room temperature yields compound Iv.

Although certain exemplary embodiments are depicted and described aboveand herein, it will be appreciated that a compounds of the invention canbe prepared according to the methods described generally above usingappropriate starting materials, and according to methods known in theart. For example, in certain embodiments, compounds as described hereinwherein R¹ is hydrogen, and R² is pyrazolyl, exemplary procedures andcompounds can be found in WO02/22607, WO 02/22604, WO 02/066461, WO02/22601, WO 02/22603, WO 02/22608, WO 02/022605, or WO 02/22602.

5. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

As discussed above, the present invention provides compounds that areinhibitors of voltage-gated sodium ion channels and/or calcium channels,and thus the present compounds are useful for the treatment of diseases,disorders, and conditions including, but not limited to acute, chronic,neuropathic, or inflammatory pain, arthritis, migrane, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,epilepsy or epilepsy conditions, neurodegenerative disorders,psychiatric disorders such as anxiety and depression, myotonia,arrythmia, movement disorders, neuroendocrine disorders, ataxia,multiple sclerosis, irritable bowel syndrome, and incontinence.Accordingly, in another aspect of the present invention,pharmaceutically acceptable compositions are provided, wherein thesecompositions comprise any of the compounds as described herein, andoptionally comprise a pharmaceutically acceptable carrier, adjuvant orvehicle. In certain embodiments, these compositions optionally furthercomprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative thereof. According to thepresent invention, a pharmaceutically acceptable derivative includes,but is not limited to, pharmaceutically acceptable salts, esters, saltsof such esters, or any other adduct or derivative which uponadministration to a patient in need is capable of providing, directly orindirectly, a compound as otherwise described herein, or a metabolite orresidue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of a voltage-gated sodium ion channel orcalcium channel.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In yet another aspect, a method for the treatment or lessening theseverity of acute, chronic, neuropathic, or inflammatory pain,arthritis, migrane, cluster headaches, trigeminal neuralgia, herpeticneuralgia, general neuralgias, epilepsy or epilepsy conditions,neurodegenerative disorders, psychiatric disorders such as anxiety anddepression, myotonia, arrythmia, movement disorders, neuroendocrinedisorders, ataxia, multiple sclerosis, irritable bowel syndrome,incontinence, visceral pain, osteoarthritis pain, postherpeticneuralgia, diabetic neuropathy, radicular pain, sciatica, back pain,head or neck pain, severe or intractable pain, nociceptive pain,breakthrough pain, postsurgical pain, or cancer pain is providedcomprising administering an effective amount of a compound, or apharmaceutically acceptable composition comprising a compound to asubject in need thereof. In certain embodiments, a method for thetreatment or lessening the severity of acute, chronic, neuropathic, orinflammatory pain is provided comprising administering an effectiveamount of a compound or a pharmaceutically acceptable composition to asubject in need thereof. In certain other embodiments, a method for thetreatment or lessening the severity of radicular pain, sciatica, backpain, head pain, or neck pain is provided comprising administering aneffective amount of a compound or a pharmaceutically acceptablecomposition to a, subject in need thereof. In still other embodiments, amethod for the treatment or lessening the severity of severe orintractable pain, acute pain, postsurgical pain, back pain, or cancerpain is provided comprising administering an effective amount of acompound or a pharmaceutically acceptable composition to a subject inneed thereof.

In certain embodiments of the present invention an “effective amount” ofthe compound or pharmaceutically acceptable composition is that amounteffective for treating or lessening the severity of one or more ofacute, chronic, neuropathic, or inflammatory pain, arthritis, migrane,cluster headaches, trigeminal neuralgia, herpetic neuralgia, generalneuralgias, epilepsy or epilepsy conditions, neurodegenerativedisorders, psychiatric disorders such as anxiety and depression,myotonia, arrythmia, movement disorders, neuroendocrine disorders,ataxia, multiple sclerosis, irritable bowel syndrome, incontinence,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, or cancer pain.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of oneor more of acute, chronic, neuropathic, or inflammatory pain, arthritis,migrane, cluster headaches, trigeminal neuralgia, herpetic neuralgia,general neuralgias, epilepsy or epilepsy conditions, neurodegenerativedisorders, psychiatric disorders such as anxiety and depression,myotonia, arrythmia, movement disorders, neuroendocrine disorders,ataxia, multiple sclerosis, irritable bowel syndrome, incontinence,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, or cancer pain. The exact amount required will varyfrom subject to subject, depending on the species, age, and generalcondition of the subject, the severity of the infection, the particularagent, its mode of administration, and the like. The compounds of theinvention are preferably formulated in dosage unit form for ease ofadministration and uniformity of dosage. The expression “dosage unitform” as used herein refers to a physically discrete unit of agentappropriate for the patient to be treated. It will be understood,however, that the total daily usage of the compounds and compositions ofthe present invention will be decided by the attending physician withinthe scope of sound medical judgment. The specific effective dose levelfor any particular patient or organism will depend upon a variety offactors including the disorder being treated and the severity of thedisorder; the activity of the specific compound employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the patient; the time of administration, route of administration, andrate of excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed, and like factors well known in the medical arts. Theterm “patient”, as used herein, means an animal, preferably a mammal,and most preferably a human.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms are prepared by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas inhibitors of voltage-gated sodium ion channels or calcium channels,preferably N-type calcium channels. In one embodiment, the compounds andcompositions of the invention are inhibitors of one or more of NaV1.1,NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, orCaV2.2, and thus, without wishing to be bound by any particular theory,the compounds and compositions are particularly useful for treating orlessening the severity of a disease, condition, or disorder whereactivation or hyperactivity of one or more of NaV1.1, NaV1.2, NaV1.3,NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 is implicatedin the disease, condition, or disorder. When activation or hyperactivityof NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8,NaV1.9, or CaV2.2, is implicated in a particular disease, condition, ordisorder, the disease, condition, or disorder may also be referred to asa “NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 orNaV1.9-mediated disease, condition or disorder” or a “CaV2.2-mediatedcondition or disorder”. Accordingly, in another aspect, the presentinvention provides a method for treating or lessening the severity of adisease, condition, or disorder where activation or hyperactivity of oneor more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7,NaV1.8, NaV1.9, or CaV2.2 is implicated in the disease state.

The activity of a compound utilized in this invention as an inhibitor ofNaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9,or CaV2.2 may be assayed according to methods described generally in theExamples herein, or according to methods available to one of ordinaryskill in the art.

In certain exemplary embodiments, compounds of the invention are usefulas inhibitors of NaV1.8. In other embodiments, compounds of theinvention are useful as inhibitors of NaV1.8 and CaV2.2. In still otherembodiments, compounds of the invention are useful as inhibitors ofCaV2.2. In yet other embodiments, compounds of the invention are usefulas dual inhibitors of NaV1.8 and a TTX-sensitive ion channel such asNaV1.3 or NaV1.7.

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the present invention can be employed incombination therapies, that is, the compounds and pharmaceuticallyacceptable compositions can be administered concurrently with, prior to,or subsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents that arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”. For example, exemplary additional therapeutic agentsinclude, but are not limited to: nonopioid analgesics (indoles such asEtodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such saNabumetone; oxicams such as Piroxicam; para-aminophenol derivatives,such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen,Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylatessuch as Asprin, Choline magnesium trisalicylate, Diflunisal; fenamatessuch as meclofenamic acid, Mefenamic acid; and pyrazoles such asPhenylbutazone); or opioid (narcotic) agonists (such as Codeine,Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine,Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol,Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesicapproaches may be utilized in conjunction with administration of one ormore compounds of the invention. For example, anesthesiologic(intraspinal infusion, neural blocade), neurosurgical (neurolysis of CNSpathways), neurostimulatory (transcutaneous electrical nervestimulation, dorsal column stimulation), physiatric (physical therapy,orthotic devices, diathermy), or psychologic (cognitivemethods-hypnosis, biofeedback, or behavioral methods) approaches mayalso be utilized. Additional appropriate therapeutic agents orapproaches are described generally in The Merck Manual, SeventeenthEdition, Ed. Mark H. Beers and Robert Berkow, Merck ResearchLaboratories, 1999, and the Food and Drug Administration website,www.fda.gov, the entire contents of which are hereby incorporated byreference.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, the presentinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. In still anotheraspect, the present invention includes an implantable device coated witha composition comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. Suitable coatingsand the general preparation of coated implantable devices are describedin U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings aretypically biocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccarides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to inhibiting one or more ofNaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9,or CaV2.2 activity in a biological sample or a patient, which methodcomprises administering to the patient, or contacting said biologicalsample with a compound of formula I or, a composition comprising saidcompound. The term “biological sample”, as used herein, includes,without limitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5,NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 activity in a biologicalsample is useful for a variety of purposes that are known to one ofskill in the art. Examples of such purposes include, but are not limitedto, the study of sodium ion channels in biological and pathologicalphenomena; and the comparative evaluation of new sodium ion channelinhibitors.

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

EXAMPLES Synthesis of Exemplary Compounds of the Invention Example 1

In a 2 L three-necked round-bottomed flask equipped with an overheadstirrer and reflux condenser, anthranilamide 1 (20.0 g, 147 mmol) andpotassium carbonate (28.4 g, 206 mmol) was suspended in 1 L dry etherand heated to reflux. o-Anisoyl chloride (32.5 g, 191 mmol) was addedslowly to the refluxing mixture. After 3 hours at reflux, the reactionmixture was allowed to cool to room temperature, the ether was removedunder reduced pressure, and the resulting residue was filtered andwashed with water. The resulting solid was then suspended in 600 mL of5% aq. NaOH solution and boiled for one hour. The reaction was allowedto cool to room temperature, then neutralized with acetic acid, uponwhich quinazilinone 2 was precipitated. Product 2 was collected byfiltration, washed with water, and dried overnight in vacuo to yield 27g (73%) of pure 2.

LC/MS (10-99%) M/Z 253.0 retention time 3.22 min; ¹H NMR (DMSO) δ3.86(s, 3H), δ7.09 (t, 1H), δ 7.18 (d, 1H), δ 7.53 (m, 2H), δ 7.70 (m, 2H),δ 7.80 (m, 1H), δ 8.14 (d, 1H), δ 12.11 (s, 1H); ¹³C NMR (DMSO) δ 55.75,δ 111.86, δ 120.89, δ 120.97, δ 122.74, δ 125.75, δ 126.45, δ 127.26, δ130.41, δ 132.13, δ 134.32, δ 148.97, δ 152.48, δ 157.12, δ 161.35

Quinazolinone 2 (20.0 g, 79.3 mmol) was suspended in 500 mL dry benzenein a 1 L round-bottomed flask equipped with a reflux condenser.N,N-Dimethylanaline (14.4 g, 119 mmol) was added and the reaction wasrefluxed for 30 minutes under nitrogen. Upon cooling to roomtemperature, phosphorus oxychloride (12.2 g, 79.3 mmol) was added andthe reaction mixture was then refluxed for an additional 3 hours undernitrogen. The mixture was cooled to room temperature, poured over ice,and neutralized with saturated aqueous sodium bicarbonate. The solutionwas then extracted four times with toluene and the combined organiclayers dried over magnesium sulfate, filtered, and concentrated in vacuoto a reddish-brown solid. The resulting 4-chloroquinazoline 3 waspurified via flash chromatography (40% hexanes, 60% dichloromethane) toafford 20 g (93%) 3 as a yellow solid.

LC/MS (40-99%) M/Z 271.4 retention time 2.49 min; ¹HNMR (CDCl₃) δ3.89(s, 3H), δ57.06 (d, 1H), δ 7.09 (d, 1H), δ 7.45 (m, 1H), δ 7.71 (m, 1H),δ 7.80 (m, 1H), δ 7.95 (m, 1H), δ 8.17 (d, 1H), δ 8.30 (d, 1H); ¹³C NMR(CDCl₃) δ 56.3 (d), δ 112.15 (d), δ 121.0 (s), δ 122.29 (s), δ 125.97(s), δ 126.76 (s), δ 127.25 (d), δ 128.71 (d), δ 132.10 (m), δ 135.26(s), δ 151.16 (s), δ 158.19 (s), δ 161.02 (s), δ 162.58 (s).

A 500 mL two-necked round-bottomed flask equipped with an additionfunnel was charged with 4-Chloroquinazoline 3 (5.00 g, 18.5 mmol) and 80mL dry dichloromethane under nitrogen. The mixture was cooled to ˜78° C.and 92 mL of 1M boron tribromide in dichloromethane was added dropwisevia the addition funnel. The cooling bath was removed and the reactionallowed to stir for three hours at room temperature. The mixture wasthen cooled to 0° C. and slowly neutralized with saturated aqueoussodium bicarbonate, extracted 3 times with dichloromethane, and thecombined organic solutions dried over magnesium sulfate, filtered, andconcentrated in vacuo to a yellow solid. The residue was promptlydissolved in 30 mL of 2:1 dry THF/CH₂Cl₂, then treated with 2 Mdimethlyamine in THF (46.3 mL, 92.5 mmol). After 30 min the solvent wasremoved under reduced pressure, the residue partitioned betweendichloromethane and water, and the aqueous solution extracted 4 timeswith dichloromethane. The combined organic solutions were dried overmagnesium sulfate, filtered, and concentrated in vacuo to an orangesolid. Recrystallization from ethanol gave 2.61 g (53%) yellowcrystalline 4.

LC/MS (10-99%) M/Z 266.0 retention time 2.59 min; ¹H NMR (DMSO) δ3.32(s,), δ3.45 (s, 61-1), δ 6.93 (m, 2H), δ 7.35 (m, 1H), δ 7.46 (m, 1H), δ7.78 (m, 2H), δ 8.21 (d, 1H), δ 8.43 (d, 1H); ¹³C NMR (DMSO) δ 41.62,113.77, 117.18, 118.25, 118.97, 124.75, 126.15, 126.51, 128.96, 132.36,133.11, 149.09, 159.22, 160.74, 161.69.

HCl salt:

A 250 mL round-bottomed flask was charged with quinazoline 4 (1.0 g, 3.8mmol), 100 mL dry ether, 11 mL dry methanol, then sealed with a septumand placed in a sonicator with the bath temperature at 43° C. Uponcomplete dissolution of 4, 2 M ethereal HCl solution was added (1.9 mL,3.8 mmol), causing immediate precipitation of 5. The solvent was removedin vacuo, and the salt twice re-suspended in dry ether, concentrated,and dried in vacuo. After drying overnight under vacuum, 1.13 g (98%) 5was obtained as a pale yellow solid.

M/Z 266.0 retention time 2.59 min; ¹H NMR (DMSO) δ3.59 (s, 6H), δ 7.02(m, 1H), δ 7.19 (d, 1H), S 7.49 (m, 1H), S 7.64 (m, 1H), δ 7.96 (m, 1H),δ 8.05 (d, 1H), δ 8.20 (d, 1H), δ 8.35 (d, 1H); ¹³C NMR (DMSO) δ 42.37,112.07, 117.19, 119.23, 121.09, 126.15, 127.48, 130.45, 134.01, 134.67,155.37, 158.61, 160.97.

Example 2 Synthesis of2-(2-Methoxy-phenyl)-7-trifluoromethyl-3H-quinazolin-4-one

2-(2-Methoxy-benzoylamino)-4-trifluoromethyl-benzoic acid2-Amino-4-trifluoro-benzoic acid (3.84 g, 18.73 mmol) was dissolved in30 ml dry 1,4-Dioxane followed by the slow addition of O-Anisoylchloride (3.3 ml, 24.35 mmol), then triethylamine (7.85 ml, 56.19 mmol)and stirred under a nitrogen atmosphere at room temperature for 2 hours.Solvent was remove under reduced pressure and organic was partitionedbetween water and EtOAc and the pH was adjusted to 3 with HCl. Organiclayer was separated, dried over MgSO4, filtered and concentrated to anoff white solid. Recovered 6.35 g 100% yield. LC/MS (10-99%) M/Z 339.9,retention time 3.58 minutes.

2-(2-Methoxy-benzoylamino)-4-trifluoromethyl-benzamide2-(2-Methoxy-benzoylamino)-4-trifluoromethyl-benzoic acid (7.04 g, 20.77mmol) was suspended in 0.5M solution of ammonia in 1,4-Dioxane (125 ml,62.31 mmol), followed by the addition of triethylamine (5.78 ml, 41.54mmol) then BOP reagent (12 g, 27.0 mmol) and stirred at room temperaturefor 16 hours. The product was collected by vacuum filtration and washedwith water. The desired product was dried on the lyophilizer for 24 h.Recovered 3.8 g as a white solid. LC/MS (10-99%) M/Z 339.1, retentiontime 2.93 minutes.

2-(2-Methoxy-phenyl)-7-trifluoromethyl-3H-quinazolin-4-one2-(2-Methoxy-benzoylamino)-4-trifluoromethyl-benzamide (3.8 g, 11.24mmol) was suspended in 145 ml 5% aqueous NaOH solution then refluxed frothree hours at 120° C. The reaction was cooled to room temperature andadjusted to pH 4 causing the desired product to precipitate fromsolution. Solid was collected by vacuum filtration as a white solid anddried on the lyophilizer for 24 h. White solid 2.7 g, 75% yield. LC/MS(10-99%) M/Z 321.1, retention time 3.25 minutes.

Synthesis of 2-(2-Methoxy-phenyl)-7-methyl-3H-quinazolin-4-one

N-(2-Cyano-5-methyl-phenyl)-2-methoxy-benzamide 2-Amino-4-methylanthronitrile (50.0 g, 378.3 mmol) was dissolved in 1 L dry pyridine andcooled to 0° C. O-Anisoyl chloride (63.0 ml, 453.96 mmol) was addeddropwise over a 40 minute period and the reaction was allowed to warm toroom temperature and stirred under a nitrogen atmosphere for 16 hours.The reaction was poured over 2 L of ice and the product formed aprecipitate. The product was collected by vacuum filtration and driedfor 3 days to produce the desired product a fluffy tan solid. Recovered92.0 g 91% yield. LC/MS (10-99%) M/Z 267.2, retention time 3.34 minutes.

2-(2-Methoxy-phenyl)-7-methyl-3H-quinazolin-4-oneN-(2-Cyano-5-methyl-phenyl)-2-methoxy-benzamide (47.0 g, 176.5 mmol) wassuspended in 1 L of ethanol followed by the addition of a 6M aqueousNaOH solution (326 ml), then a 30% solution of H₂O₂ (100 ml). Thereaction was refluxed for 3 hours, cooled to room temperature and pouredover an equal volume of ice. The solution was adjusted to pH3.5 and theproduct precipitated from solution. Desired product was collected byvacuum filtration and dried on the lyophilizer for 24 h. 22.4 g, 48%yield. LC/MS (10-99%) M/Z 267.0, retention time 2.54 minutes.

5-Fluoro-4-methyl-anthranilic acid

2-Amino-5-fluoro-4-methyl-benzoic acid. Chloral hydrate (76 g) wasdissolved in 1 L water and subsequently 1 kg Na₂SO₄, 94.1 g H₂NOH.HCl,and 51.3 g 4-fluoro-3-methyl aniline in 250 ml 5% aq. HCl were added.The suspension was heated to boiling and kept boiling for 1 minute.After cooling down to room temperature, the solid was filtered off andwashed twice with warm water (40° C.). Yield after drying overnight at60° C. under vacuum was 275 g, which was used without furtherpurification or drying. The 275 g of crude product was slowly poured in500 ml of concentrated H₂SO₄ at 50° C., such that the temperature waskept below 75° C. After completion of addition, the dark/purple solutionwas heated to 85° C. for 15 minutes. After cooling down to roomtemperature, the solution was poured in 2 L of ice water and was leftstanding for an half hour. The red solid was filtered and washed twicewith cold water. Subsequently, the solid was dried under vacuum at 70°C. Yield: 69.9 g (quantitatively from 4-fluoro-3-methyl aniline) of amixture of two regio isomers: 5-fluoro and 3-fluoro 3-methyl-isatin in aratio of about 55:45. The mixture of isatins (69.4 g) was dissolved in 1L 1N aq. NaOH and subsequently 100 ml of 30% aq. H₂O₂ was added dropwise, keeping the temperature below 30° C. After completion of addition,the mixture was heated to 45° C. until evolution of gas ceased. Thesolution was cooled to room temperature, filtered and acidified withglacial acetic acid. The precipitate formed was filtered off, washedtwice with water and air-dried 45° C. Yield: 29.4 g of5-fluoro-4-methyl-anthranilic acid iii.

2-Amino-5-trifluoromethyl-benzoic acid. 4-(trifluoromethyl)aniline (25g, 0.15 mol) was dissolved in THF (275 mL), then treated with Bocanhydride (41 g, 0.19 mol), ET₃N (19 g, 0.19 mol), and4-(dimethylamino)pyridine (0.1 g, 0.8 mmol). The mixture was refluxedfor 3 hours, the solvents removed in vacuo, and the organic residuedissolved in EtOAc, washed with 1 M NaOH, then 1 M HCl, then dried andconcentrated. The resulting product was recrystallized from heptaneyielding 39 g final product as a white solid. The solid (0.15 mol) wasdissolved in THF (350 mL) and cooled to −78° C. under nitrogen, thentreated dropwise with BuLi (1.6 M in hexane, 282 mL, 0.45 mol). After 1h, the solution was warmed to 0° C. and held for 1.5 h. The mixture waspoured onto excess solid CO₂ and stirred overnight at RT. Afterpartitioning against 1 M HCl, the THF layer was evaporated and theresidue dissolved in EtOAc, washed with 1 M HCl, then dried andconcentrated. The solid product was triturated with hexan to yield thefinal product as a white solid (15.8 g). LC/MS retention time 2.70 min,m/z (obs, M−H)=304.1. Finally the Boc anthranilate (11.3 g) wasdissolved in CH2CL2 (26 mL) and treated with TFA (21 mL). After stirringat RT for 2 h, the solution was dried in vacuo, the resulting residuedissolved in toluene (100 mL), concentrated to dryness, and thedissolution/drying process repeated twice more, yielding the desiredproduct as a white solid (10.8 g), LC/MS retention time 1.2 min, m/z(obs, M−H)=204.0.

2-Amino-5-bromo-benzamide. The isatoic anhydride (15 g, 0.062 mol) wascombined with 1 M aq. NH₄OH (340 mL) and stirred for 2 d at RT. Thesolid product was collected by filtration and dried in vacuo (6.6 g).LC/MS retention time 2.47 min, m/z obs=215.2.

To a stirring suspension of benzoyleneurea 1 (10.0 g, 61.7 mmol) andphosphorus oxychloride (20 ml) in a 500 mL three-necked round-bottomedflask equipped with a magnetic stirrer and reflux condenser, was addedN,N-dimethylaniline (7.80 ml, 61.7 mmol) in a single portion. Thesuspension was heated at reflux for 3 hours and slowly formed a lightred solution. The solution was concentrated under reduced pressure andthe residue was poured onto ice (100 g). The solution was basified topH=9.0 using concentrated aqueous sodium bicarbonate solution. Themixture was partitioned between CH₂Cl₂ and H₂O. The organic portion wasdried (MgSO₄) and evaporated to dryness under reduced pressure. Theresidue was dissolved in anhydrous THF (75 ml) and cooled to 0° C.Dimethylaniline (67.7 mL, 135 mmol, 2.0 M in THF) was added dropwise,with stirring, over a period of 30 minutes. The solution was thenstirred at 0° C. for 1 hour. The solution was concentrated under reducedpressure and the residue was purified by silica gel chromatography using(70% hexanes, 30% ethyl acetate) to obtain 2 (7.90 g, 38.1 mmol, 62%yield) as a white solid.

¹H NMR (CDCl₃) δ3.43 (s, 6H), 7.40 (t, 1H), 7.69 (t, 1H), 7.78 (d, 1H),8.02 (d, 1H); M+1 (obs)=208.0; R_(t)=2.26.

A 5 mL microwave reaction vessel was charged with a mixture of 2 (100mg, 0.48 mmol), 2-methoxyphenylboronic acid (96 mg, 0.63 mmol),tetrakis(triphenylphosphine)palladium(0) (55 mg, 0.048 mmol), sodiumcarbonate (1.20 mL, 0.48 mmol, 0.40 M aqueous solution), andacetonitrile (1.20 mL). The vessel was sealed and heated, with stirring,at 170° C. for 10 minutes via microwave irradiation. The organic portionwas concentrated under reduced pressure and the residue was purified bysilica gel chromatography using (80% hexanes, 20% ethyl acetate) toobtain 3 (120 mg, 0.43 mmol, 89% yield) as a white solid.

¹H NMR (CDCl₃) δ3.32 (s, 6H), 3.81 (s, 3H), 6.89-7.02 (m, 2H), 7.28-7.34(m, 2H), 7.62 (t, 1H), 7.75 (d, 1H), 7.89 (d, 1H), 7.95 (d, 1H); M+1(obs)=280.2; R_(t)=2.46.

2-Chloro-4-dimethylaminoquinazoline-7-carboxylic acid methyl ester. Astirring suspension of2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-7-carboxylic acid methyl ester(12.2 g, 55.4 mmol), N,N-dimethylaniline (14.0 mL, 110.8 mmol), andPOCl₃ (25 mL), under N₂, was heated at 100° C. for 15 minutes. Thesolution was evaporated to dryness under reduced pressure and theresidual oil was poured into ice-water (800 mL). The mixture was madestrongly basic by the addition of 50% aqueous NaOH solution at 0° C. Themixture was partitioned between CH₂Cl₂ and H₂O and the organic portionwas evaporated to dryness under reduced pressure. The residue waspurified by silica gel chromatography using 70% hexanes/30% EtOAc toobtain the intermediate chloride as a white solid (5.1 g, 19.8 mmol).The obtained intermediate was dissolved in CH₂Cl₂ (100 mL). The solutionwas cooled to 0° C. followed by the addition of Et₃N (5.5 mL, 39.6 mmol)and dimethylamine hydrochloride (1.6 g, 19.8 mmol). The mixture was thenstirred at 0° C. for 30 minutes. The mixture was evaporated to drynessand the obtained residue was purified via silica gel chromatographyusing 70% hexanes/30% EtOAc to obtain the desired amine as a white solid(3.3 g, 12.4 mmol, 11% yield). LC/MS (10-99%) M/Z 268.0 retention time2.85 min.

6-Fluoro-N4,N4-dimethylquinazoline-2,4-diamine. A stirring mixture of(2-chloro-6-fluoro-quinazolin-4-yl)-dimethylamine (50 mg, 0.22 mmol),lithium bis(trimethylsilyl)amide (260 μL, 0.26 mmol, 1.0 M in hexanes),Pd₂(dba)₃ (20 mg, 0.022 mmol), 2-(dicyclohexyl)phosphinobiphenyl (19 mg,0.053 mmol), and THF (1.0 mL) was heated in a sealed tube via microwaveirradiation at 65° C. for 1.5 hours. 1.0 N aqueous HCl solution (3.0 mL)was added and the mixture was stirred at room temperature for 30minutes. The mixture was partitioned between H₂O and EtOAc. The organicportion was evaporated to dryness under reduced pressure. The obtainedresidue was purified via silica gel chromatography using 95% CH₂Cl₂/5%MeOH to obtain the desired amine as a tan solid (40 mg, 19.4 mmol, 88%yield). LC/MS (10-99%) M/Z 206.9 retention time 1.18 min.

1-(4-Dimethylamino-6-fluoroquinazolin-2-yl)-pyrrolidine-2,5-dione. Astirring mixture of 6-fluoro-N4,N4-dimethylquinazoline-2,4-diamine (30.0mg, 0.13 mmol), succinic anhydride (12 mg, 0.12 mmol), and p-dioxane(500 μL) was heated in a sealed tube via microwave irradiation at 170°C. for 20 minutes. The mixture was purified via HPLC to obtain thedesired succinate as a TFA salt (40 mg, 0.10 mmol, 76% yield). LC/MS(10-99%) M/Z 289.3 retention time 2.01 min.

1-(6-Fluoro-4-pyrrolidin-1-yl-quinazolin-2-yl)-pyrrolidin-2-one. Astirring mixture of 6-fluoro-4-pyrrolidin-1-yl-quinazolin-2-ylamine(30.0 mg, 0.14 mmol), 4-chlorobutyryl chloride (17 μL, 0.15 mmol), Et₃N(42 μL, 0.30 mmol), and p-dioxane (500 μL) was heated in a sealed tubevia microwave irradiation at 170° C. for 20 minutes. The mixture waspurified via HPLC to obtain the desired lactam as a TFA salt (45 mg,0.11 mmol, 81% yield). LC/MS (10-99%) M/Z 301.2 retention time 2.24 min.

1-(4-Dimethylamino-6-fluoro-quinazolin-2-yl)-1H-pyrrole-3-carbaldehyde.A stirring mixture of 6-fluoro-N4,N4-dimethylquinazoline-2,4-diamine(20.0 mg, 0.10 mmol), 2,5-dimethyoxy-3-tetrahydrofurancarboxaldehyde (43μL, 0.30 mmol), and AcOH (500 μL) was heated at 90° C. for 30 minutes.The mixture was evaporated to dryness and the obtained residue waspurified via silica gel chromatography using 70% hexanes/30% EtOAc toobtain the desired aldehyde as a white solid (15 mg, 0.05 mmol, 50%yield). LC/MS (10-99%) M/Z 285.1 retention time 3.23 min.

(6-Methoxy-2-pyrrol-1-yl-quinazolin-4-yl)-dimethyl-amine. To a stirringsolution pyrrole (310 mg, 4.6 mmol) and DMF (5.0 mL), under N₂, wasadded NaH (170 mg, 4.2 mmol, 60% in mineral oil). The mixture wasstirred at room temperature for 10 minutes. To this solution was added(2-chloro-6-methoxyquinazolin-4-yl)dimethylamine (1.0 g, 4.2 mmol). Themixture was heated in a sealed tube via microwave irradiation at 220° C.for 20 minutes. The mixture was evaporated to dryness and the obtainedresidue was purified via silica gel chromatography using 70% hexanes/30%EtOAc to obtain the desired aldehyde as a white solid (15 mg, 0.05 mmol,50% yield). LC/MS (10-99%) M/Z 269.0 retention time 2.39 min.

[2-(2-Chloro-pyrrol-1-yl)-6-methoxyquinazolin-4-yl]dimethyl-amine. To astirring solution of(6-methoxy-2-pyrrol-1-yl-quinazolin-4-yl)dimethyl-amine (25 mg, 0.09mmol) and THF (2.0 mL), under N₂, was added N-chlorosuccinimide (13 mg,0.09 mmol). The solution was stirred at room temperature for 17 hours.The mixture was purified via HPLC to obtain the desired chloropyrrole asa TFA salt (23 mg, 0.06 mmol, 62% yield). LC/MS (10-99%) M/Z 303.0retention time 2.71 min.

2-[4-(4-Aminopiperidin-1-yl)-7-methylquinazolin-2-yl]-phenol. To astirring solution of 2-(4-Chloro-7-methylquinazolin-2-yl)-phenol (100mg, 0.35 mmol), Et₃N (72 μL, 0.52 mmol), and CH₂Cl₂ (300 μL) under N₂,was added 4-aminopiperidine (54 μL, 0.52 mmol). The mixture was stirredat room temperature for 2 hours. The mixture was evaporated to drynessunder reduced pressure. The residue was purified by silica gelchromatography using 98% CH₂Cl₂/2% MeOH to obtain the desired amine as awhite solid (11 mg, 0.31 mmol, 89% yield). LC/MS (10-99%) M/Z 349.3retention time 2.22 min.

Ethanesulfonic acid{1-[2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl]-piperidin-4-yl}-amide.To a stirring solution of2-[4-(4-Aminopiperidin-1-yl)-7-methylquinazolin-2-yl]-phenol (30 mg,0.09 mmol), Et₃N (25 μL, 0.18 mmol), and CH₂Cl₂ (500 μL) under N₂, wasadded ethanesulfonyl chloride (10 μL, 0.09 mmol). The mixture wasstirred at room temperature for 3 hours. The mixture was purified viaHPLC to obtain the desired sulfonamide as a TFA salt (33 mg, 0.06 mmol,68% yield). LC/MS (10-99%) M/Z 427.3 retention time 2.80 min.

3-{1-[2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl]-piperidin-4-yl}-1,1-dimethylsulfonylurea.To a stirring solution of2-[4-(4-Aminopiperidin-1-yl)-7-methylquinazolin-2-yl]-phenol (35 mg,0.11 mmol), Et₃N (30 μL, 0.22 mmol), and CH₂Cl₂ (300 μL) under N₂, wasadded dimethylsulfamoyl chloride (12 μL, 0.11 mmol). The mixture wasstirred at room temperature for 17 hours. The mixture was purified viaHPLC to obtain the desired sulfonylurea as a TFA salt (44 mg, 0.08 mmol,71% yield). LC/MS (10-99%) M/Z 442.4 retention time 2.84 min.

{1-[2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl]-piperidin-4-yl}-carbamicacid isobutyl ester. To a stirring solution of2-[4-(4-Aminopiperidin-1-yl)-7-methylquinazolin-2-yl]-phenol (30 mg,0.09 mmol), Et₃N (25 μL, 0.18 mmol), and CH₂Cl₂ (300 μL) under N₂, wasadded isobutylchloroformate (12 μL, 0.09 mmol). The mixture was stirredat room temperature for 1 hour. The mixture was purified via HPLC toobtain the desired carbamate as a TFA salt (27 mg, 0.05 mmol. 58%yield). LC/MS (10-99%) M/Z 435.2 retention time 3.21 min.

Isobutylcarbamic acid1-[2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl]-piperidin-4-yl ester. Toa stirring solution of1-[2-(2-Methoxyphenyl)-7-methylquinazolin-4-yl]-piperidin-4-ol (100 mg,0.30 mmol) and THF (500 μL) under N₂, was added phosgene (317 μL, 0.60mmol, 20% in toluene). The mixture was stirred at room temperature for15 minutes. Isobutylamine (300 μL, 3.0 mmol) was added dropwise over a 2minute period followed by stirring at room temperature for 1 hour. Themixture was evaporated to dryness and the obtained residue was purifiedvia silica gel chromatography using 97% CH₂Cl₂/3% MeOH to obtain thedesired carbamate intermediate as a clear oil (90 mg, 0.20 mmol). To astirring solution of the carbamate intermediate (90 mg, 0.20 mmol) andCH₂Cl₂ (15 mL), under N₂, at −78° C., was added BBr₃ (0.60 mL, 0.60mmol, 1.0 M in CH₂Cl₂) dropwise over a period of 2 minutes. The mixturewas then allowed to warm to room temperature and was then heated at 50°C. for 15 minutes. The mixture was poured into a saturated aqueousNaHCO₃ solution (80 mL) and the organic portion was evaporated todryness. The residue was purified via HPLC to obtain the desiredcarbamate as a TFA salt (66 mg, 0.12 mmol, 39% yield). LC/MS (10-99%)M/Z 435.3 retention time 3.08 min.

N-{1-[2-(2-Hydroxy-phenyl)-7-methylquinazolin-4-yl]-piperidin-4-yl}-3-methylbutyramide.To a stirring solution of2-[4-(4-Aminopiperidin-1-yl)-7-methylquinazolin-2-yl]-phenol (35 mg,0.11 mmol), Et₃N (30 μL, 0.22 mmol), and CH₂Cl₂ (300 μL) under N₂, wasadded isovaleryl chloride (14 μL, 0.11 mmol). The mixture was stirred atroom temperature for 17 hours. The mixture was purified via HPLC toobtain the desired sulfonamide as a TFA salt (37 mg, 0.07 mmol, 59%yield). LC/MS (10-99%) M/Z 419.3 retention time 2.77 min.

Synthesis of 2-(4-Ethoxy-quinazolin-2-yl)-phenol

2-(4-Ethoxy-quinazolin-2-yl)-phenol. 2-(4-Chloro-quinazolin-2-yl)-phenol(50 mg, 0.196 mmol) was placed in a microwave tube charged with a stirbar and dissolved 0.5 ml dry dichloromethane, followed by the additionof 2 ml dry ethanol. Tube was sealed with a cap and heated at 160 to200° C. for one hour in CEM microwave. Solvent was removed under reducedpressure, reconstituted organic in DMSO and purified by Gilson HPLC. Thedesired compound was concentrated to a white solid as the TFA salt.LC/MS (10-99%) M/Z 267.2, retention time 2.57 minutes.

Synthesis 2-(4-Dimethylamino-quinazolin-2-yl)-6-methyl-phenol

[2-(2-Methoxy-3-methyl-phenyl)-quinazolin-4-yl]-dimethyl-amine To astirring solution of[2-(2-Methoxy-phenyl)-quinazolin-4-yl]-dimethyl-amine (200 mg, 0.72mmol) in dry THF under an argon atmosphere at −78° C. was added dropwisea 1.6M solution of nBuLi in hexanes (0.671 ml, 1.074 mmol). After 10minutes MeI (0.076 ml, 1.22 mmol) was added and the reaction was allowedto warm to room temperature. After 10 minutes at room temperature thereaction was quenched with a saturated aqueous solution of NH₄Cl andpartitioned between aqueous and EtOAc. Organic phase was separated,dried over MgSO₄, filtered and concentrated to a yellow oil. Purified byflash chromatograpy 10% EtOAc/90% hexanes to afford product as a whitesolid. Recovered 146 mg 50% yield. LC/MS (10-99%) M/Z 294.0, retentiontime 3.23 minutes.

2-(4-Dimethylamino-quinazolin-2-yl)-6-methyl-phenol To a stirringsolution of [2-(2-Methoxy-phenyl)-quinazolin-4-yl]-dimethyl-amine (54mg, 0.184 mmol) in CH₂Cl₂ at −78° C. under a nitrogen atmosphere wasadded BBr₃ (0.92 ml, 0.92 mmol). The reaction was allowed to warm toroom temperature and the heated at 45° C. for 4 hours. The reaction wasallowed to cool to room temperature and then quenched with an aqueoussolution of NaHCO₃ until pH8. Organic layer was separated, dried overMgSO₄, filtered, and concentrated to a yellow solid. Purified by GilsonHPLC and desired product was isolated as the TFA salt. LC/MS (10-99%)M/Z 280.2, retention time 2.55 minutes.

Synthesis of 2-(4-Dimethylamino-quinazolin-2-yl)-4-morpholin-4-yl-phenol

[2-(2-Methoxy-5-morpholin-4-yl-phenyl)-quinazolin-4-yl]-dimethyl-amineTo a tube charged with a stirbar was added Pd₂(dba)₃ (51.1 mg, 0.0558mmol), biphenyl-2-yl-di-tert-butyl-phosphane (67 mg, 0.223 mmol), NaOtBu(80 mg, 0.837 mmol) in 2 ml dry toluene was added4-Bromo-2-(4-dimethylamino-quinazolin-2-yl)-phenol (200 mg, 0.558 mmol)and morpholine (0.073 ml, 0.837 mmol). The reaction was sealed with ascrew cap and heated at 100° C. in an oil bath for 16 h. Purified byflash chromatograpy 30%-60% EtOAc/hexanes to afford product as a whitesolid. Recovered 100 mg 49% yield. LC/MS (10-99%) M/Z 365.0, retentiontime 2.07 minutes.

2-(4-Dimethylamino-quinazolin-2-yl)-4-morpholin-4-yl-phenol To astirring solution of[2-(2-Methoxy-5-morpholin-4-yl-phenyl)-quinazolin-4-yl]-dimethyl-amine(109 mg, 0.299 mmol) in CH₂Cl₂ at −78° C. under a nitrogen atmospherewas added BBr₃ (1.5 ml, 1.5 mmol). The reaction was allowed to warm toroom temperature and was heated at 40° C. for 2 hours. The reaction wasquenched with an aqueous solution of NaHCO₃ until pH 8. Organic layerwas separated, dried over MgSO₄, filtered, and concentrated to a yellowsolid. Purified by Gilson HPLC and desired product was isolated as theTFA salt. LC/MS (10-99%) M/Z 351.4, retention time 1.89 minutes.

Synthesis of 2-(4-Dimethylamino-quinazolin-2-yl)-4-methyl-phenol

[2-(2-Methoxy-5-methyl-phenyl)-quinazolin-4-yl]-dimethyl-amine To astirring solution of[[2-(5-Bromo-2-methoxy-phenyl)-quinazolin-4-yl]-dimethyl-amine (200 mg,0.558 mmol) in dry THF under an argon atmosphere at −78° C. was addeddropwise a 1.6M solution of nBuLi in hexanes (0.76 ml, 1.23 mmol). After10 minutes MeI (0.054 ml, 1.23 mmol) was added and the reaction wasallowed to warm to room temperature. After 10 minutes at roomtemperature the reaction was quenched with a saturated aqueous solutionof NH₄Cl and partitioned between aqueous and EtOAc. Organic phase wasseparated, dried over MgSO₄, filtered and concentrated to a yellow oil.Purified by flash chromatograpy 30% EtOAc/70% hexanes to afford productas a white solid. Recovered 146 mg 89% yield. LC/MS (10-99%) M/Z 294.4,retention time 2.64 minutes.

2-(4-Dimethylamino-quinazolin-2-yl)-4-methyl-phenol To a stirringsolution of[2-(2-Methoxy-5-methyl-phenyl)-quinazolin-4-yl]-dimethyl-amine (146 mg,0.498 mmol) in CH₂Cl₂ at −78° C. under a nitrogen atmosphere was addedBBr₃ (2.49 ml, 2.49 mmol). The reaction was allowed to warm to roomtemperature and was complete after 2 hours. The reaction was quenchedwith an aqueous solution of NaHCO₃ until pH8. Organic layer wasseparated, dried over MgSO₄, filtered, and concentrated to a yellowsolid. Purified by Gilson HPLC and desired product was isolated as theTFA salt. LC/MS (10-99%) M/Z 280.2, retention time 2.65 minutes.

Synthesis of 2-(2′-methylsulfonylphenyl)-4-dimethylaminoquinazoline

2-(2′-methylsulfonylphenyl)-4-dimethylaminoquinazoline. A 2 mL PersonalChemistry Microwave reaction vessel with a stir bar was charged with2-(2′-bromophenyl)-4-dimethylaminoquinazoline (0.020 g, 61 mmol), copper(I) iodide (0.017 g, 91 mmol), sodium methanesulfinate (0.010 g, 97mmol), and 0.5 mL of DMF.¹ This mixture was irradiated at 180° C. for 10min. After cooling, water and ether were added, and an extraction wasperformed. The ether layer was then filtered through celite and thenextracted once again, using approximately 20% NH₄OH to remove additionalcopper. After concentrating, the product was redissolved in a 50/50solution of DMSO/MeOH. Purification was conducted on LC/MS to providethe TFA salt. LC/MS (10-99%) M/Z 328.3, retention time 3.03 min.

Synthesis of 2-(2′-anilino)-4-dimethylaminoquinazoline

2-(2′-anilino)-4-dimethylaminoquinazoline. Zinc powder (1.18 g, 18.0mmol) was added to a solution of2-(2′-nitrophenyl)-4-dimethylaminoquinazoline (0.530 g, 1.80 mmol) inacetic acid (10.9 mL, 190 mmol) at 0° C. The reaction mixturesolidified, but then began to stir again after the ice bath wasremoved.^(3,4) The reaction mixture was stirred for three hours at roomtemperature. Deionized water (approximately 10 mL) was then added, and asolution formed, followed by formation of a precipitate. This solutionwas then taken slightly basic with NaHCO₃(aq). The product was extractedthree times with ethyl acetate, dried with MgSO₄, filtered, andconcentrated. Approximately 20 mg of the product was redissolved in a50/50 solution of DMSO/MeOH and purified by LC/MS to provide the bis-TFAsalt. LC/MS (10-99%) M/Z 265.0, retention time 2.81 min.

Synthesis of 2-(2′-ethylsulfanylphenyl)-4-dimethylaminoquinazoline

2-(2′-ethylsulfanylphenyl)-4-dimethylaminoquinazoline. Potassiumcarbonate (0.052 g, 0.374 mmol) and ethanethiol (0.055 mL, 0.748 mmol)were added to a solution of2-(2′-fluorophenyl)-4-dimethylaminoquinazoline (0.020 g, 0.0748 mmol) inN,N-dimethylformamide (1 mL) in a microwave reaction vessel with a stirbar. This mixture was irradiated in the microwave at 135° C. for 1.5hours. The resulting mixture was filtered and then purified by LC/MS toprovide the TFA salt. LC/MS (10-99%) M/Z 310.2, retention time 3.27 min.

Synthesis of 2-(2′-cyanophenyl)-4-dimethylaminoquinazoline

2-(2′-cyanophenyl)-4-dimethylaminoquinazoline. A round bottom flask wascharged with 2-(2′-bromophenyl)-4-dimethylaminoquinazoline (0.010 g,0.0305 mmol), potassium cyanide (0.0040 g, 0.0609 mmol),tetrakis(triphenylphosphine)palladium(0) (0.0018 g, 0.00152 mmol),copper(I)iodide (0.00058 g, 0.00305 mmol), and acetonitrile (0.50 mL)and heated to reflux overnight.⁵ After cooling to room temperature,ethyl acetate was added and filtered through celite. An extraction wasthen performed, using ammonium hydroxide (approximately 20%) to removeadditional copper. After being concentrated, the product was redissolvedin a 50/50 solution of DMSO/MeOH and purified by LC/MS to provide theTFA salt. LC/MS (10-99%) M/Z 275.2, retention time 2.85 min.

Synthesis of 2-(2′-isopropenylphenyl)-4-dimethylaminoquinazoline

2-(2′-isopropenylphenyl)-4-dimethylaminoquinazoline. A 0.5 M solution ofisopropenyl magnesium bromide (0.898 mL, 0.449 mmol) was added to asolution of 2-(2′-fluorophenyl)-4-dimethylaminoquinazoline (0.040 g,0.150 mmol) in ethylene glycol dimethyl ether (1 mL) in a microwavevessel with a stir bar. The sample was irradiated in the microwave for 5min at 170° C. Deionized water (approximately 2 mL) was then added. Anextraction was then performed with ether. After being concentrated, theproduct was redissolved in a 50/50 solution of DMSO/MeOH and purified byLC/MS to provide the TFA salt. LC/MS (10-99%) M/Z 289.8, retention time3.23 min.

Synthesis of 2-(2′-hydroxyphenyl)-4-dimethylamino-6-methoxyquinazoline

2-(2′-hydroxyphenyl)-4-dimethylamino-6-methoxyquinazoline. A microwavereaction vessel with a stir bar was charged with2-(2′-acetoxyphenyl)-4-dimethylamino-6-bromoquinazoline (0.100 g, 0.259mmol), copper(I) iodide (0.0245 g, 0.129 mmol), N,N-dimethylformamide(0.90 mL), and a 0.5 M solution of sodium methoxide (1.04 mL, 0.518mmol) in methanol. The sample was irradiated in the microwave for 20 minat 150° C. After cooling, the sample was diluted with ether and thenfiltered through celite. Next, an extraction was performed, usingammonium hydroxide (approximately 20%) to remove additional copper.After being concentrated, the product was redissolved in a 50/50solution of DMSO/MeOH and purified by LC/MS (20-99%) to provide the TFAsalt. Approximate yield=60% (by LC/MS). LC/MS (10-99%) M/Z 296.4,retention time 2.31 min.

Synthesis of4-Fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acidmethyl ester

3-Bromo-4-fluoro-benzoic acid methyl ester. 3-Bromo-4-fluoro-benzoicacid (2.5 g, 11.42 mmol) was placed in a 100 ml round bottom flaskcharged with a stir bar, sealed with a septum and placed under anitrogen atmosphere and dissolved in 9 ml dry THF and 3 ml dry MeOH. A2.0M solution of TMSdiazomethane in ether (6.28 ml, 12.56 mmol) wasadded dropwise to the stirring solution of the acid. Conversion of theacid to the ester was complete after twenty minutes according to LC/MSanalysis. The solvent was removed under reduced pressure and product wasused without further purification. Recovered a light oil (2.66 g, 100%yield) LC/MS (10-99%) M/Z 234, retention time 3.09 minutes.

4-Fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acidmethyl ester. To a round bottom flask charged with a stir bar was added3-Bromo-4-fluoro-benzoic acid methyl ester (1.66 g, 7.12 mmol),Bis(pinacolato)diboron (2.2 g, 8.5 mmol), potassium acetate (2.1 g, 21.3mmol), and (0.35 g, 0.43 mmol)[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II), complexwith dichloromethane (1:1). The reaction was sealed with a septum,evacuated and the placed under a nitrogen atmosphere, followed by theaddition of 20 ml of dry DMSO. The reaction was heated at 80° C. in anoil bath for two hours. The reaction was allowed to cool to roomtemperature and partitioned between ethyl acetate and water. Organiclayer was separated, and the aqueous layer was extracted two more times.All organics were combined, dried over MgSO₄, filtered and concentratedunder reduced pressure to a black oil. The product was purified by flashchromatography using a gradient of EtOAc/Hexanes 0 to 60%, to afford thedesired product as a white solid (1.48 g, 74% yield). LC/MS (10-99%) M/Z281.4, retention time 2.73 minutes.

The quinazoline 1 (1.5 g, 3.0 mmol) was dissolved in THF (150 mL). Aftercooling to −78° C., t-BuLi (1.7 M in heptane, 1.76 mL) was addeddropwise. After stirring for 10 min at −78° C., CO₂ (crushed) was addedto the solution, then warmed up to RT and stirred for 30 min. Quenchedthe reaction with H₂O (100 mL), diluted with EtOAc (100 mL), The organiclayer was dried, concentrated, purified by flash chromatography (1%-10%MeOH/DCM) to obtain 2 (600 mg, 43% yield).

Synthesis of2-(2′-hydroxyphenyl)-4-dimethylamino-6-morpholinoquinazoline

2-(2′-hydroxyphenyl)-4-dimethylamino-6-morpholinoquinazoline. A dryreaction tube with a septa screw cap under N₂ was charged withtris(dibenzylideneacetone)dipalladium(0) (0.012 g, 13.0 mmol),2,2′-bis(diphenylphosphino)-1,1′-binapthyl (0.024 g, 38.8 mmol), cesiumcarbonate (0.097 g, 298 mmol), toluene (0.25 mL),2-(2′-acetoxyphenyl)-4-dimethylamino-6-bromoquinazoline (0.050 g, 129mmol), and morpholine (23 μL, 259 mmol), in that order.² This mixturewas then heated to 80° C. for 24 hours. After cooling, the mixture wasdiluted with ether, filtered through celite and silica gel, andconcentrated. The product was redissolved in a 50/50 solution ofDMSO/MeOH and purified by LC/MS to provide the bis-TFA salt. LC/MS(10-99%) M/Z 351.0, retention time 2.75 min.

The quinazoline 1 (0.2 g, 0.62 mmol) was dissolved in CH₃CN (5 mL).After cooling to −10° C. (ice/NaCl), CCl₄, DIEA and DMAP were added.After stirring for 10 min, a solution of dibenzyl phosphite in CH₃CN (2mL) was slowly added over 10 min. Stirring was continued at −10° C. for2 h, then at RT for 24 h. Quenched by addition of 0.5 M K₂HPO₄, dilutedwith water (15 mL), extracted with DCM (30 mL), dried, concentrated,purified by flash chromatography (100% DCM) to obtain 2 (168 mg, 47%yield) as a colorless oil. LC/MS (10-99%) M/Z 586.0 retention time 2.54min.

To a solution of the quinazoline 2 (0.168 g, 0.29 mmol) in DCM (1.5 mL)was added TMSBr (0.079 mL, 0.61 mmol) at 0° C. The reaction was stirredfor 1 h at 0° C., then for 1 h at RT. The reaction was quenched withwater (3 mL) and stirred for 15 min. The aqueous layer was washed withEtOAc (5 mL), and dried with lyophilizer overnight to give desiredproduct 3 as white foam (0.14 g. 100% yield). LC/MS (10-99%) M/Z 406.0retention time 3.32 min.

To a solution of the quinazoline 3 (0.14 g, 0.36 mmol) in MeOH (3 mL)was added NaOMe (1.44 mL, 0.72 mmol) at RT. The reaction was stirredovernight at RT. The reaction mixture was concentrated using rotavap(25° C.), then the residue was taken up with water (75 mL) and washedwith EtOAc (3×50 mL). The aqueous phase was dried with lyophilizer togive final product 4 (0.14 g, 98% yield) as solid. LC/MS (10-99%) M/Z406.0 retention time 3.32 min.

2-{7-Methyl-4-[methyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amino]-quinazolin-2-yl}-phenol

[2-(2-Methoxy-phenyl)-7-methyl-quinazolin-4-yl]-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amine4-Chloro-2-(2-methoxy-phenyl)-7-methyl-quinazoline (400 mg, 1.48 mmol)was dissolved in 10 ml dry DMF followed by the addition ofC-(5-Methyl-[1,3,4]oxadiazol-2-yl)-methylamine oxalate (234 mg, 1.48mmol) then triethylamine (413 μL, 2.96 mmol). After 6 hours the reactionwas complete, partitioned between EtOAc and water. The organic phase wasseparated, dried over MgSO₄, filtered and concentrated to an oil.Purified by flash chromatography 60% EtOAc/40% hexanes to afford thedesired product a white solid. Recovered 290 mg 56% yield. LC/MS(10-99%) M/Z 348.4, retention time 2.17 minutes.

[2-(2-Methoxy-phenyl)-7-methyl-quinazolin-4-yl]-methyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amineTo a stirring suspension of freshly washed sodium hydride (42 mg, 1.04mmol) in dry DMF at 0° C. under a nitrogen atmosphere was added the[2-(2-Methoxy-phenyl)-7-methyl-quinazolin-4-yl]-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amine(180 mg, 0.518 mmol, in 5 ml DMF). After 30 minutes at 0° C., MeI (74μL, 1.19 mmol) was added and the reaction was allowed to warm to roomtemperature. After one hour the reaction was quenched with water andextracted 3 times with EtOAc. Organics were combined, dried over MgSO₄,filtered and concentrated to a yellow oil. Purified by flashchromatography 50/50 EtOAc/hexanes to afford the desired product as aclear oil. 128 mg, 66% yield. LC/MS (10-99%) M/Z 376.1, retention time2.06 minutes.

2-{7-Methyl-4-[methyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amino]-quinazolin-2-yl}-phenolTo a stirring solution of[2-(2-Methoxy-phenyl)-7-methyl-quinazolin-4-yl]-methyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amine(128 mg, 0.341 mmol) in 7 ml dry CH₂Cl₂ at −78° C. under a nitrogenatmosphere was added BBr₃ (1.71 ml, 1.71 mmol) dropwise. The reactionwas allowed to warm to room temperature and after three hours thereaction was quenched with a saturated aqueous solution of NaHCO₃ untilpH8. The organic was separated, dried over MgSO₄, filtered andconcentrated to a light yellow oil. Purified by Gilson HPLC and compoundwas isolated as the TFA salt. LC/MS (10-99%) M/Z 362.3, retention time2.12 minutes.

To a solution of the quinazoline (187 mg, 0.63 mmol) in CH₂Cl₂ (5 mL)was added pyridine (0.11 mL, 1.36 mmol) at RT. After cooling to 0° C. asolution of acetyl chloride (50 μL, 0.70 mmol) in CH₂Cl₂ (5 mL) wasadded, stirring was continued for 45 Min at RT and the solvent wasremoved in vacuo. Chromatography over silica (hexanes/EtOAc/NEt₃:2:1:0.05) afforded compound 1 as a white solid (90 mg, 42%). Compound 1:LC/MS (10-99%): m/z=338 [M+H]⁺, R_(t): 3.28 min.

Other compounds of general formula I have been prepared by methodssubstantially similar to those described above. The characterizationdata for these compounds is summarized in Table 3 below, and compoundnumbers correspond to the compounds depicted in Table 2.

TABLE 3 Exemplary Characterization Data for Compounds of Formula I Cmpd# LC_MASS_PLUS 15 308.40 16 306.00 164 320.00 194 389.20 195 404.20 198302.00, 302.20, 302.00 202 328.20, 328.20, 328.00 241 268.30 250 346.00252 310.00 253 344.00 254 319.00 255 333.00 256 348.00 257 319.00 258289.80 259 249.80, 250.40 260 386.20 261 357.00 262 275.20 263 358.00264 325.00 265 296.60, 296.40, 296.40 266 345.20 267 310.20, 310.00 268351.00 269 310.00 270 340.10 271 298.10 272 314.00 273 328.20 274 284.00275 300.10 276 328.10 277 286.90 278 306.00 279 280.20 280 380.00 281334.00, 334.00 282 336.00 283 351.00 284 336.00, 336.00 285 322.00,322.00, 322.00, 322.00 286 307.00 287 378.00 288 405.00 289 349.00 290292.00 291 322.00 292 342.00 293 294.00 294 358.20 295 374.00 296 382.40297 256.80 298 239.00 299 339.80 300 279.00 301 386.00 302 307.20 303318.00 304 296.20 305 278.00 306 291.80 307 239.00 308 289.00 309 270.00310 402.20 311 342.00 312 342.00 313 320.20 314 309.00 315 399.00 316318.00 317 332.00 318 332.00 319 315.00 320 329.00 321 343.00 322 357.00323 342.00 324 342.00 325 368.00, 368.10 326 352.00 327 369.80 328456.20 329 381.80 330 384.00 331 395.80 332 322.00, 322.20 333 284.00334 334.00 335 280.00 336 296.00 337 306.00 338 286.80 339 286.80 340329.40 341 356.20 342 329.40 343 463.20 344 491.60 345 353.20 346 315.80347 359.00 348 402.20 349 341.80 350 359.80 351 384.80 352 371.80 353369.60 354 343.00 355 441.00 356 353.80 357 314.00 358 320.00 359 323.00360 289.00 361 322.20 362 400.00 363 386.00 364 390.00 365 306.00 366385.80 367 370.00 368 374.00 369 320.00 370 320.00 371 322.00 372 320.00373 308.00, 308.00 374 340.00 375 356.00 376 280.20, 280.00 377 300.40,300.00 378 282.00 379 326.20 380 351.20 381 338.20 382 336.20 383 309.20384 407.40 385 334.20 386 323.40 387 380.20 388 294.00 389 350.00 390345.00 391 326.00 392 352.80 393 323.00 394 286.00 395 344.00 396 340.00397 326.00 398 314.00 399 312.00 400 343.20 401 354.00 402 340.00 403282.00 404 285.00 405 283.20 406 292.00 407 464.00 408 298.00 409 273.00410 326.20 411 326.20 412 356.00 413 359.20 414 355.00 415 338.00 416370.00 417 328.00 418 298.20 419 279.80 420 281.80 421 340.90 422269.30, 269.20 423 303.00 424 372.80 425 272.80 426 307.00 427 322.20428 324.20 429 284.00, 285.00 430 286.00 431 429.00 432 439.00 433443.00 434 456.00 435 486.00 436 326.20 437 328.00 438 253.00 439 257.00440 299.20 441 273.00 442 414.40 443 286.00 444 302.20 445 330.00 446328.20 447 355.40 448 412.00 449 286.00 450 338.20, 338.00 451 352.20452 267.00 453 326.20 454 284.20 455 309.20 456 399.20 457 312.00 458340.20 459 302.00 460 316.00 461 344.00 462 328.00 463 378.00 464 316.00465 327.80 466 371.80, 371.60 467 355.60 468 356.80 469 359.00 470435.20 471 368.00 472 344.00 473 282.20 474 281.20 475 355.00 476 302.20477 316.20 478 344.20 479 328.20 480 378.00 481 316.20 482 282.00 483286.00 484 328.00 485 324.20 486 353.80 487 377.80 488 365.00 489 339.80490 267.00 491 281.00 492 310.20 493 352.20 494 342.00 495 328.00 496402.20, 402.40 497 439.20 498 421.00 499 367.00 500 397.20 501 365.00502 270.00 508 290.90 516 403.40 517 403.40 518 403.60 519 403.40 520408.40 521 409.20 522 432.40 523 432.20 524 431.40 525 432.40 526 432.40527 437.40 528 437.40 529 446.40 530 452.40 531 463.00 532 370.00 533382.20 534 384.20 535 398.20 536 437.40 537 439.40 538 439.40 539 439.20540 377.40 541 384.00 542 386.00 543 391.20 544 391.20 545 397.40 546397.40 547 397.40 548 411.40 549 368.20 550 420.20 551 441.40 552 446.00553 449.40 554 394.00 555 450.20 556 330.00 557 332.20 558 334.00 559346.00 560 348.00 561 372.00 562 383.20 563 383.20 564 383.20 565 383.20566 387.80 567 388.80 568 403.40 569 412.00 570 412.00 571 412.00 572349.20 573 361.00 574 375.20 575 389.20 576 411.20 577 411.20 586 281.00587 342.40 588 356.00 589 358.20 590 365.20, 365.20 591 369.20, 369.20592 370.00 593 372.40 594 383.20, 383.20, 383.20, 383.20 595 384.00 596391.20 597 397.40 598 337.80 599 350.00 600 352.00 601 376.00 602 387.20603 391.80 604 393.00 605 416.00 606 416.20 607 416.00 608 353.00 609415.20 610 415.20 611 416.20 612 421.00 613 430.20 614 431.20 615 436.20616 447.00 617 459.20 618 493.00 619 353.80 620 353.80 621 365.80 622367.80 623 367.80 624 367.80 625 383.00 626 409.40 627 421.00 628 423.20629 423.20 630 423.20 631 429.20, 429.00 632 430.00 633 435.20 634437.00 635 437.40 636 479.20 637 361.00 638 362.20 639 364.80 640 366.00641 366.00 642 367.20 643 367.80 644 368.00 645 370.00 646 375.20 647375.20 648 375.20 649 375.20 650 375.20 651 381.00 652 381.00 653 381.20654 381.20 655 381.20 656 388.20 657 395.00 658 395.20 659 418.00 660352.00 661 365.80 662 365.80 663 385.80 664 404.20 665 404.00 666 406.00667 425.20 668 430.20 669 430.20 670 446.00 671 429.40 672 433.20 673457.20 674 430.00 675 418.20 676 436.20 677 378.00 678 269.80 679 411.20680 427.20 681 399.80 682 420.20 683 420.00 684 434.20 685 454.20 686399.80 687 414.20 688 420.00 689 432.00 690 367.80, 367.80 691 323.00692 324.00 693 326.00 694 326.00 695 326.00 696 338.00 697 340.00 698342.00 699 342.00 700 349.00 701 353.20 702 353.00 703 353.00 704 353.20705 353.20 706 354.00 707 354.00 708 356.00 709 355.80 710 355.80 711367.00 712 367.20 713 367.20 714 367.20 715 368.00 716 367.80 717371.80, 373.10 718 375.00 719 381.00 720 382.00 721 382.20 722 383.20723 385.00 724 389.20 725 390.00 726 393.20 727 393.20 728 397.20 729400.20 730 403.40 731 404.20 732 407.40 733 411.20 734 413.20 735 415.40736 416.20 737 419.00 738 419.20 739 421.00 740 423.20 741 428.20 742429.40 743 430.20 744 431.40 745 431.20 746 441.40 747 446.00 748 450.20749 432.00 750 470.20 751 352.00 752 352.00 753 352.00 754 374.00 755373.80 756 374.00 757 378.00 758 378.00 759 378.00 760 416.20 761 429.20762 432.00 763 441.40 764 470.20 765 477.00 766 326.00 767 366.00 768365.80 769 388.20 770 326.00 771 352.20 772 364.20 773 380.80 774 397.20775 407.40 776 413.20 777 415.20 778 421.00 779 429.20 780 350.00 781283.80 782 294.00 783 296.00 784 298.00 785 312.00 786 314.00 787 314.00788 324.00 789 328.00 790 340.00 791 343.80 792 310.00 793 347.00 794347.00 795 351.00 796 373.80 797 326.00 798 326.00 799 326.20 800 338.00801 372.00 802 372.00 803 381.80 804 377.20 805 377.20 806 377.20 807384.00 808 391.00 809 391.20 810 414.40 811 348.00 812 362.00 813 362.00814 381.80 815 399.80 816 399.80 817 402.00 818 425.80 819 426.00 820442.00 821 474.20 822 425.20 823 425.20 824 429.20 825 453.00 826 426.00827 373.80 828 407.40 829 413.00 830 423.20 831 395.80 832 416.00 833416.00 834 430.00 835 395.80 836 410.00 837 409.80 838 416.00 839364.00, 364.00 840 439.20 841 319.00 842 319.80 843 321.80 844 321.80845 322.00 846 334.00 847 336.20 848 337.80 849 337.80 850 344.80 851349.20, 349.00 852 349.20 853 349.20 854 350.00 855 350.00 856 352.20857 353.00 858 352.00 859 352.00 860 363.00 861 363.00 862 363.00 863363.20 864 363.80, 364.00 865 364.00 866 363.80 867 370.80 868 373.20869 377.00 870 378.00 871 379.20 872 385.20 873 385.80 874 385.80 875389.20 876 389.20 877 392.80, 393.20, 393.30 878 396.20 879 398.20,398.20 880 399.00 881 284.30 882 412.20 883 417.40 884 417.20 885 432.20886 417.40 887 419.20 888 357.00 889 364.40 890 371.00 891 348.00,348.20 892 360.20 893 386.20 894 393.20 895 409.00 896 417.40 897 425.00898 346.00 899 412.40 900 426.20 901 427.40 902 443.20 903 455.20 904489.20 905 350.20 906 350.20 907 362.00 908 364.00 909 364.00 910 364.00911 378.60 912 405.60 913 419.40 914 419.20 915 425.00 916 431.40 917433.40 918 433.40 919 475.20 920 358.20 921 361.00 922 362.00 923 362.00924 363.20 925 364.00 926 366.00 927 371.20 928 371.40 929 371.20 930377.20 931 377.20 932 368.00, 368.00 933 400.20 934 400.00 935 403.40936 407.60 937 409.20 938 411.20 939 412.00 940 415.20 941 417.00 942419.20 943 424.40 944 425.20 945 426.00 946 427.00 947 427.60 948 437.20949 442.20 950 446.00 951 348.00 952 348.00 953 348.00 954 370.00 955370.00 956 370.00 957 374.00 958 374.20 959 374.00 960 412.40 961425.00, 425.00 962 430.00 963 437.60 964 440.00 965 466.40 966 473.00967 364.20, 364.00 968 290.20 969 292.00 970 306.20 971 308.60 972310.00 973 324.20 974 336.00 975 340.00 976 306.60 977 343.00 978 347.00979 370.00 980 322.20 981 322.40, 322.00 982 356.00 983 368.40 984368.00 985 378.20 986 405.60 987 409.40 988 416.20 989 420.00 990 423.40991 427.40 992 429.20 993 431.40 994 435.40 995 439.20 996 445.20 997447.00 998 466.40 999 432.40 1000 369.00 1001 381.00 1002 409.20 1003431.60 1004 432.40 1005 509.40 1006 384.00 1007 384.00 1008 425.40 1009445.20 1010 451.20 1011 452.40 1012 495.40 1013 381.00 1014 382.00 1015411.20 1016 444.40 1017 457.40 1018 384.00 1019 352.40 1020 368.00 1021391.20 1022 391.20 1023 328.40 1024 434.40 1025 382.00 1026 358.20 1027369.20 1028 369.20 1029 383.20 1030 340.20 1031 409.40 1032 420.40 1033368.00 1034 445.20 1035 330.40 1036 340.00 1037 356.00 1038 359.80 1039363.20 1040 367.00 1041 390.00 1042 342.00 1043 342.60 1044 388.40 1045343.80 1048 455.00 1049 338.00 1050 324.20 1051 433.60 1052 427.00 1053443.20 1054 398.20 1055 435.20 1056 415.20 1057 417.40 1058 393.00 1059361.00 1060 422.00 1065 385.20 1066 353.10 1067 354.10 1068 367.10 1069380.90 1070 388.30 1071 353.10 1072 368.10 1073 410.00 1074 383.90 1075429.10 1083 352.00, 351.90, 352.30, 352.20, 352.30, 352.30, 352.00 1084350.00 1085 363.00 1086 377.00 1087 384.00, 384.00 1088 380.00 1089362.00 1090 410.00 1091 426.00 1092 370.00 1101 293.00 1102 307.00 1103334.00 1106 374.10, 374.00 1107 379.30 1108 421.10, 421.00, 421.00 1109435.50 1110 407.50 1111 399.30 1112 413.30 1113 427.30 1114 391.30 1115405.50 1116 377.30 1117 441.50, 441.00 1118 410.90 1119 335.90 1120355.80, 355.90 1121 394.90 1122 407.50 1123 343.00, 341.90 1124 427.101125 396.00 1127 461.30 1128 393.80 1133 443.00 1134 419.80 1135 453.001136 378.00 1137 463.00, 463.00 1138 457.00 1141 504.00 1142 420.20 1143422.20 1144 436.00 1145 448.20 1146 370.10 1147 457.50 1148 463.10,463.10 1151 435.80 1152 450.00 1153 407.60 1155 518.10 1156 482.00 1157485.50 1158 432.20 1159 473.10 1160 432.20 1161 468.50 1162 393.80 1163444.00 1164 450.00 1165 511.00 1166 467.00 1167 363.30 1168 463.00 1169482.00 1170 415.00 1171 467.00 1172 511.00 1173 491.00 1174 495.00 1175365.90 1176 380.30 1179 321.80 1180 560.00 1181 337.20 1182 280.00 1183259.20 1184 500.20, 500.20, 500.20 1185 353.00 1186 526.80 1190 350.201191 392.00 1192 376.00 1193 404.20 1194 462.20 1195 427.20 1196 407.401197 391.10

Methods:

(A) Micromass MUX LCT 4 channel LC/MS, Waters 60F pump, Gilson 215 4probe autosampler, Gilson 849 injection module, 1.5 mL/min/column flowrate, 10-99% CH₃CN (0.035% TFA)/H₂O (0.05 TFA) gradient, Phenomenex Luna5u C18 columns (50×4.60 mm), Waters MUX UV-2488 UV detector, Cedex 75ELSD detectors.

(B) PESciex API-150-EX LC/MS, Shimadzu LC-8A pumps, Gilson 215autosampler, Gilson 819 injection module, 3.0 mL/min flow rate, 10-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gradient, Phenomenex Luna 5u C18column (50×4.60 mm), Shimadzu SPD-10A UVN is detector, Cedex 75 ELSDdetector.

(C) PESciex API-150-EX LC/MS, Shimadzu LC-8A pumps, Gilson 215autosampler, Gilson 819 injection module, 3.0 mL/min flow rate, 40-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gradient, Phenomenex Luna 5u C18column (50×4.60 mm), Shimadzu SPD-10A UVN is detector, Cedex 75 ELSDdetector.

Assays for Detecting and Measuring NaV Inhibition Properties ofCompounds

A) Optical Methods for Assaying NaV Inhibition Properties of Compounds:

Compounds of the invention are useful as antagonists of voltage-gatedsodium ion channels. Antagonist properties of test compounds wereassessed as follows. Cells expressing the NaV of interest were placedinto microtiter plates. After an incubation period, the cells werestained with fluorescent dyes sensitive to the transmembrane potential.The test compounds were added to the microtiter plate. The cells werestimulated with either a chemical or electrical means to evoke a NaVdependent membrane potential change from unblocked channels, which wasdetected and measured with trans-membrane potential-sensitive dyes.Antagonists were detected as a decreased membrane potential response tothe stimulus. The optical membrane potential assay utilizedvoltage-sensitive FRET sensors described by Gonzalez and Tsien (SeeGonzalez, J. E. and R. Y. Tsien (1995) “Voltage sensing by fluorescenceresonance energy transfer in single cells” Biophys J 69(4): 1272-80, andGonzalez, J. E. and R. Y. Tsien (1997) “Improved indicators of cellmembrane potential that use fluorescence resonance energy transfer” ChemBiol 4(4): 269-77) in combination with instrumentation for measuringfluorescence changes such as the Voltage/Ion Probe Reader (VIPR®) (See,Gonzalez, J. E., K. Oades, et al. (1999) “Cell-based assays andinstrumentation for screening ion-channel targets” Drug Discov Today4(9): 431-439).

B) VIPR® Optical Membrane Potential Assay Method with ChemicalStimulation

Cell Handling and Dye Loading

24 hours before the assay on VIPR, CHO cells endogenously expressing aNaV1.2 type voltage-gated NaV are seeded in 96-well poly-lysine coatedplates at 60,000 cells per well. Other subtypes are performed in ananalogous mode in a cell line expressing the NaV of interest.

-   1) On the day of the assay, medium is aspirated and cells are washed    twice with 225 μL of Bath Solution #2 (BS#2).-   2) A 15 uM CC2-DMPE solution is prepared by mixing 5 mM coumarin    stock solution with 10% Pluronic 127 1:1 and then dissolving the mix    in the appropriate volume of BS#2.-   3) After bath solution is removed from the 96-well plates, the cells    are loaded with 80 μL of the CC2-DMPE solution. Plates are incubated    in the dark for 30 minutes at room temperature.-   4) While the cells are being stained with coumarin, a 15 μL oxonol    solution in BS#2 is prepared. In addition to DiSBAC₂(3), this    solution should contain 0.75 mM ABSC1 and 30 μL veratridine    (prepared from 10 mM EtOH stock, Sigma #V-5754).-   5) After 30 minutes, CC2-DMPE is removed and the cells are washed    twice with 225 μL of BS#2. As before, the residual volume should be    40 μL.-   6) Upon removing the bath, the cells are loaded with 80 μL of the    DiSBAC₂(3) solution, after which test compound, dissolved in DMSO,    is added to achieve the desired test concentration to each well from    the drug addition plate and mixed thoroughly. The volume in the well    should be roughly 121 μL. The cells are then incubated for 20-30    minutes.-   7) Once the incubation is complete, the cells are ready to be    assayed on VIPR® with a sodium addback protocol. 120 μL of Bath    solution #1 is added to stimulate the NaV dependent depolarization.    200 μL tetracaine was used as an antagonist positive control for    block of the NaV channel.

Analysis of VIPR® Data:

Data are analyzed and reported as normalized ratios ofbackground-subtracted emission intensities measured in the 460 nm and580 nm channels. Background intensities are then subtracted from eachassay channel. Background intensities are obtained by measuring theemission intensities during the same time periods from identicallytreated assay wells in which there are no cells. The response as afunction of time is then reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{14mu} {nm}} - {background}_{460\mspace{14mu} {nm}}} \right)}{\left( {{intensity}_{580\mspace{14mu} {nm}} - {background}_{580\mspace{14mu} {nm}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final(R_(f)) ratios. These are the average ratio values during part or all ofthe pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus R=R_(f)/R_(i) is thencalculated. For the Na⁺ addback analysis time windows, baseline is 2-7sec and final response is sampled at 15-24 sec.

Control responses are obtained by performing assays in the presence of acompound with the desired properties (positive control), such astetracaine, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls arecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$

where R is the ratio response of the test compoundSolutions [mM]Bath Solution #1: NaCl 160, KCl 4.5, CaCl₂ 2, MgCl₂ 1, HEPES 10, pH 7.4with NaOHBath Solution #2 TMA-Cl 160, CaCl₂ 0.1, MgCl₂ 1, HEPES 10, pH 7.4 withKOH (final K concentration ˜5 mM)CC2-DMPE: prepared as a 5 mM stock solution in DMSO and stored at −20°C.DiSBAC₂(3): prepared as a 12 mM stock in DMSO and stored at −20° C.ABSC1: prepared as a 200 mM stock in distilled H₂O and stored at roomtemperature

Cell Culture

CHO cells are grown in DMEM (Dulbecco's Modified Eagle Medium; GibcoBRL#10569-010) supplemented with 10% FBS (Fetal Bovine Serum, qualified;GibcoBRL #16140-071) and 1% Pen-Strep (Penicillin-Streptomycin; GibcoBRL#15140-122). Cells are grown in vented cap flasks, in 90% humidity and10% CO₂, to 100% confluence. They are usually split by trypsinization1:10 or 1:20, depending on scheduling needs, and grown for 2-3 daysbefore the next split.

C) VIPR® Optical Membrane Potential Assay Method with ElectricalStimulation

The following is an example of how NaV1.3 inhibition activity ismeasured using the optical membrane potential method#2. Other subtypesare performed in an analogous mode in a cell line expressing the NaV ofinterest.

HEK293 cells stably expressing NaV1.3 are plated into 96-well microtiterplates. After an appropriate incubation period, the cells are stainedwith the voltage sensitive dyes CC2-DMPE/DiSBAC2(3) as follows.

Reagents:

100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO

10 mM DiSBAC₂(3) (Aurora #00-100-010) in dry DMSO 10 mM CC2-DMPE (Aurora#00-100-008) in dry DMSO 200 mM ABSC1 in H₂O

Hank's Balanced Salt Solution (Hyclone #SH30268.02) supplemented with 10mM HEPES (Gibco #15630-080)

Loading Protocol:

2×CC2-DMPE=20 μM CC2-DMPE: 10 mM CC2-DMPE is vortexed with an equivalentvolume of 10% pluronic, followed by vortexing in required amount of HBSScontaining 10 mM HEPES. Each cell plate will require 5 mL of 2×CC2-DMPE.50 μL of 2×CC2-DMPE is to wells containing washed cells, resulting in a10 μM final staining concentration. The cells are stained for 30 minutesin the dark at RT.

2×DISBAC₂(3) with ABSC1=6 μM DISBAC₂(3) and 1 mM ABSC1: The requiredamount of 10 mM DISBAC₂(3) is added to a 50 ml conical tube and mixedwith 1 μL 10% pluronic for each mL of solution to be made and vortexedtogether. Then HBSS/HEPES is added to make up 2× solution. Finally, theABSC1 is added.

The 2×DiSBAC₂(3) solution can be used to solvate compound plates. Notethat compound plates are made at 2× drug concentration. Wash stainedplate again, leaving residual volume of 50 μL. Add 50 uL/well of the2×DiSBAC₂(3) w/ ABSC1. Stain for 30 minutes in the dark at RT.

The electrical stimulation instrument and methods of use are describedin ION Channel Assay Methods PCT/US01/21652, herein incorporated byreference. The instrument comprises a microtiter plate handler, anoptical system for exciting the coumarin dye while simultaneouslyrecording the coumarin and oxonol emissions, a waveform generator, acurrent- or voltage-controlled amplifier, and a device for insertingelectrodes in, well. Under integrated computer control, this instrumentpasses user-programmed electrical stimulus protocols to cells within thewells of the microtiter plate.

Reagents

Assay buffer #1

140 mM NaCl, 4.5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES, 10 mMglucose, pH 7.40, 330 mOsmPluronic stock (1000×): 100 mg/mL pluronic 127 in dry DMSOOxonol stock (3333×): 10 mM DiSBAC₂(3) in dry DMSOCoumarin stock (1000×): 10 mM CC2-DMPE in dry DMSOABSC1 stock (400×): 200 mM ABSC1 in water

Assay Protocol

-   -   1. Insert or use electrodes into each well to be assayed.    -   2. Use the current-controlled amplifier to deliver stimulation        wave pulses for 3 s. Two seconds of pre-stimulus recording are        performed to obtain the un-stimulated intensities. Five seconds        of post-stimulation recording are performed to examine the        relaxation to the resting state.

Data Analysis

Data are analyzed and reported as normalized ratios ofbackground-subtracted emission intensities measured in the 460 nm and580 nm channels. Background intensities are then subtracted from eachassay channel. Background intensities are obtained by measuring theemission intensities during the same time periods from identicallytreated assay wells in which there are no cells. The response as afunction of time is then reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{14mu} {nm}} - {background}_{460\mspace{14mu} {nm}}} \right)}{\left( {{intensity}_{580\mspace{14mu} {nm}} - {background}_{580\mspace{14mu} {nm}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final(R_(f)) ratios. These are the average ratio values during part or all ofthe pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus R=R_(f)/R_(i) is thencalculated.

Control responses are obtained by performing assays in the presence of acompound with the desired properties (positive control), such astetracaine, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls arecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$

where R is the ratio response of the test compound.

Electrophysiology Assays for NaV Activity and Inhibition of TestCompounds

Patch clamp electrophysiology was used to assess the efficacy andselectivity of sodium channel blockers in dorsal root ganglion neurons.Rat neurons were isolated from the dorsal root ganglions and maintainedin culture for 2 to 10 days in the presence of NGF (50 ng/ml) (culturemedia consisted of NeurobasalA supplemented with B27, glutamine andantibiotics). Small diameter neurons (nociceptors, 8-12 μm in diameter)have been visually identified and probed with fine tip glass electrodesconnected to an amplifier (Axon Instruments). The “voltage clamp” modehas been used to assess the compound's IC50 holding the cells at −60 mV.In addition, the “current clamp” mode has been employed to test theefficacy of the compounds in blocking action potential generation inresponse to current injections. The results of these experiments havecontributed to the definition of the efficacy profile of the compounds.

VOLTAGE-CLAMP Assay in DRG Neurons

TTX-resistant sodium currents were recorded from DRG somata using thewhole-cell variation of the patch clamp technique. Recordings were madeat room temperature (˜22° C.) with thick walled borosilicate glasselectrodes (WPI; resistance 3-4 MΩ)) using an Axopatch 200B amplifier(Axon Instruments). After establishing the whole-cell configuration,approximately 15 minutes were allowed for the pipette solution toequilibrate within the cell before beginning recording. Currents werelowpass filtered between 2-5 kHz and digitally sampled at 10 kHz. Seriesresistance was compensated 60-70% and was monitored continuouslythroughout the experiment. The liquid junction potential (−7 mV) betweenthe intracellular pipette solution and the external recording solutionwas not accounted for in the data analysis. Test solutions were appliedto the cells with a gravity driven fast perfusion system (SF-77; WarnerInstruments).

Dose-response relationships were determined in voltage clamp mode byrepeatedly depolarizing the cell from the experiment specific holdingpotential to a test potential of +10 mV once every 60 seconds. Blockingeffects were allowed to plateau before proceeding to the next testconcentration.

Solutions

Intracellular solution (in mM): Cs-F (130), NaCl (10), MgCl₂ (1), EGTA(1.5), CaCl₂ (0.1), HEPES (10), glucose (2), pH=7.42, 290 mOsm.

Extracellular solution (in mM): NaCl (138), CaCl₂ (1.26), KCl (5.33),KH₂PO₄ (0.44), MgCl₂ (0.5), MgSO₄ (0.41), NaHCO₃ (4), Na₂HPO₄ (0.3),glucose (5.6), HEPES (10), CdCl2 (0.4), NiCl2 (0.1), TTX (0.25×10⁻³).

CURRENT-CLAMP Assay for NaV Channel Inhibition Activity of Compounds

Cells were current-clamped in whole-cell configuration with a Multiplamp700A amplifier (Axon Inst). Borosilicate pipettes (4-5 MOhm) were filledwith (in mM):150 K-gluconate, 10 NaCl, 0.1 EGTA, 10 Hepes, 2 MgCl₂,(buffered to pH 7.34 with KOH). Cells were bathed in (in mM): 140 NaCl,3 KCl, 1 MgCl, 1 CaCl, and 10 Hepes). Pipette potential was zeroedbefore seal formation; liquid junction potentials were not correctedduring acquisition. Recordings were made at room temperature.

Following these procedures, representative compounds of the presentinvention were found to possess desired voltage gated sodium channelactivity and selectivity.

Assays for Detecting and Measuring CaV Inhibition Properties ofCompounds

A) Optical Methods for Assaying CaV Inhibition Properties of Compounds:

Compounds of the invention are useful as antagonists of voltage-gatedcalcium ion channels. Antagonist properties of test compounds wereassessed as follows. Cells expressing the CaV of interest were placedinto microtiter plates. After an incubation period, the cells werestained with fluorescent dyes sensitive to the transmembrane potential.The test compounds were added to the microtiter plate. The cells werestimulated with electrical means to evoke a CaV dependent membranepotential change from unblocked channels, which was detected andmeasured with trans-membrane potential-sensitive dyes. Antagonists weredetected as a decreased membrane potential response to the stimulus. Theoptical membrane potential assay Utilized voltage-sensitive FRET sensorsdescribed by Gonzalez and Tsien (See Gonzalez, J. E. and R. Y. Tsien(1995) “Voltage sensing by fluorescence resonance energy transfer insingle cells” Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y.Tsien (1997) “Improved indicators of cell membrane potential that usefluorescence resonance energy transfer” Chem Biol 4(4): 269-77) incombination with instrumentation for measuring fluorescence changes suchas the Voltage/Ion Probe Reader (VIPR®) (See, Gonzalez, J. E., K. Oades,et al. (1999) “Cell-based assays and instrumentation for screeningion-channel targets” Drug Discov Today 4(9): 431-439).

VIPR® optical membrane potential assay method with electricalstimulation

The following is an example of how CaV2.2 inhibition activity ismeasured using the optical membrane potential method. Other subtypes areperformed in an analogous mode in a cell line expressing the CaV ofinterest.

HEK293 cells stably expressing CaV2.2 are plated into 96-well microtiterplates. After an appropriate incubation period, the cells are stainedwith the voltage sensitive dyes CC2-DMPE/DiSBAC2(3) as follows.

Reagents:

100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO

10 mM DiSBAC₆(3) (Aurora #00-100-010) in dry DMSO 10 mM CC2-DMPE (Aurora#00-100-008) in dry DMSO 200 mM Acid Yellow 17 (Aurora #VABSC) in H₂O370 mM Barium Chloride (Sigma Cat# B6394) in H₂O Bath X 160 mM NaCl(Sigma Cat# S-9888) 4.5 mM KCl (Sigma Cat# P-5405) 1 mM MgCl2 (FlukaCat# 63064) 10 mM HEPES (Sigma Cat# H-4034)

pH 7.4 using NaOH

Loading Rotocol:

2×CC2-DMPE=20 μM CC2-DMPE: 10 mM CC2-DMPE is vortexed with an equivalentvolume of 10% pluronic, followed by vortexing in required amount of HBSScontaining 10 mM HEPES. Each cell plate will require 5 mL of 2×CC2-DMPE.50 μL of 2×CC2-DMPE is added to wells containing washed cells, resultingin a 10 μM final staining concentration. The cells are stained for 30minutes in the dark at RT.

2×CC2DMPE & DISBAC₆(3)=8 μM CC2DMPE & 2.5 μM DISBAC₆(3): Vortex togetherboth dyes with an equivalent volume of 10% pluronic (in DMSO). Vortex inrequired amount of Bath X with beta-cyclodextrin. Each 96well cell platewill require 5 ml of 2XCC2DMPE. Wash plate with ELx405 with Bath X,leaving a residual volume of 50 μL/well. Add 50 μL of 2XCC2DMPE &DISBAC₆(3) to each well. Stain for 30 minutes in the dark at RT.

1.5×AY17=750 μM AY17 with 15 mM BaCl₂: Add Acid Yellow 17 to vesselcontaining Bath X. Mix well. Allow solution to sit for 10 minutes.Slowly mix in 370 mM BaCl₂. This solution can be used to solvatecompound plates. Note that compound plates are made at 1.5× drugconcentration and not the usual 2×. Wash CC2 stained plate, again,leaving residual volume of 50 μL. Add 100 uL/well of the AY17 solution.Stain for 15 minutes in the dark at RT. Run plate on the optical reader.

The electrical stimulation instrument and methods of use are describedin ION Channel Assay Methods PCT/US01/21652, herein incorporated byreference. The instrument comprises a microtiter plate handler, anoptical system for exciting the coumarin dye while simultaneouslyrecording the coumarin and oxonol emissions, a waveform generator, acurrent- or voltage-controlled amplifier, and a device for insertingelectrodes in well. Under integrated computer control, this instrumentpasses user-programmed electrical stimulus protocols to cells within thewells of the microtiter plate.

Assay Protocol

Insert or use electrodes into each well to be assayed.

Use the current-controlled amplifier to deliver stimulation wave pulsesfor 3-5 s. Two seconds of pre-stimulus recording are performed to obtainthe un-stimulated intensities. Five seconds of post-stimulationrecording are performed to examine the relaxation to the resting state.

Data Analysis

Data are analyzed and reported as normalized ratios ofbackground-subtracted emission intensities measured in the 460 nm and580 nm channels. Background intensities are then subtracted from eachassay channel. Background intensities are obtained by measuring theemission intensities during the same time periods from identicallytreated assay wells in which there are no cells. The response as afunction of time is then reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{14mu} {nm}} - {background}_{460\mspace{14mu} {nm}}} \right)}{\left( {{intensity}_{580\mspace{14mu} {nm}} - {background}_{580\mspace{14mu} {nm}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final(R_(f)) ratios. These are the average ratio values during part or all ofthe pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus R=R_(f)/R_(i) is thencalculated.

Control responses are obtained by performing assays in the presence of acompound with the desired properties (positive control), such asmibefradil, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls arecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$

where R is the ratio response of the test compound.

Electrophysiology Assays for CaV Activity and Inhibition of TestCompounds

Patch clamp electrophysiology was used to assess the efficacy of calciumchannel blockers expressed in HEK293 cells. HEK293 cells expressingCaV2.2 have been visually identified and probed with fine tip glasselectrodes connected to an amplifier (Axon Instruments). The “voltageclamp” mode has been used to assess the compound's IC50 holding thecells at −100 mV. The results of these experiments have contributed tothe definition of the efficacy profile of the compounds.

VOLTAGE-CLAMP assay in HEK293 cells expressing CaV2.2

CaV2.2 calcium currents were recorded from HEK293 cells using thewhole-cell variation of the patch clamp technique. Recordings were madeat room temperature (−22° C.) with thick walled borosilicate glasselectrodes (WPI; resistance 3-4 MΩ) using an Axopatch 200B amplifier(Axon Instruments). After establishing the whole-cell configuration,approximately 15 minutes were allowed for the pipette solution toequilibrate within the cell before beginning recording. Currents werelowpass filtered between 2-5 kHz and digitally sampled at 10 kHz. Seriesresistance was compensated 60-70% and was monitored continuouslythroughout the experiment. The liquid junction potential (−7 mV) betweenthe intracellular pipette solution and the external recording solutionwas not accounted for in the data analysis. Test solutions were appliedto the cells with a gravity driven fast perfusion system (SF-77; WarnerInstruments).

Dose-response relationships were determined in voltage clamp mode byrepeatedly depolarizing the cell from the experiment specific holdingpotential to a test potential of +20 mV for 50 ms at frequencies of 0.1,1, 5, 10, 15, and 20 Hz. Blocking effects were allowed to plateau beforeproceeding to the next test concentration.

Solutions

Intracellular solution (in mM): Cs-F (130), NaCl (10), MgCl₂ (1), EGTA(1.5), CaCl₂ (0.1), HEPES (10), glucose (2), pH=7.42, 290 mOsm.

Extracellular solution (in mM): NaCl (138), BaCl₂ (10), KCl (5.33),KH₂PO₄ (0.44), MgCl₂ (0.5), MgSO₄ (0.41), NaHCO₃ (4), Na₂HPO₄ (0.3),glucose (5.6), HEPES (10).

Following these procedures, representative compounds of the presentinvention were found to possess desired N-type calcium channelmodulation activity and selectivity.

LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20110021495A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

1. A compound of formula IA:

or a pharmaceutically acceptable salt thereof, wherein: R¹ and R², takentogether with the nitrogen atom to which they are bound, form anoptionally substituted 3-12-membered monocyclic or bicyclic saturated,partially unsaturated, or fully unsaturated ring having 0-3 additionalheteroatoms independently selected from nitrogen, sulfur, or oxygen;wherein the ring formed by R¹ and R² taken together, is optionallysubstituted at one or more substitutable carbon, nitrogen, or sulfuratoms with z independent occurrences of —R⁴, wherein z is 0-5; Ring A isa 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic arylring having 0-3 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or is a 3-12-membered saturated or partiallyunsaturated monocyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein ring A is optionallysubstituted with y independent occurrences of —R⁵, wherein y is 0-5, andis additionally optionally substituted with q independent occurrences ofR^(5a), wherein q is 0-2; x is 0-4; each occurrence of R³, R⁴, and R⁵ isindependently Q-R^(X); wherein Q is a bond or is a C₁-C₆ alkylidenechain wherein up to two non-adjacent methylene units of Q are optionallyand independently replaced by —NR—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—,—COCO—, —CONR—, —NRCO—, —NRCO₂—, —SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—,—OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or—POR—; and each occurrence of R^(X) is independently selected from —R′,halogen, ═O, ═NR′, —NO₂, —CN, —OR′, —SR′, —N(R′)₂, —NR′COR′,—NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂,—SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′,—COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂,or —OPO(R′)₂; each occurrence of R^(5a) is independently an optionallysubstituted C₁-C₆aliphatic group, halogen, —OR′, —SR′, —N(R′)₂,—NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂,—OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂,—COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′,—PO(R′)₂, or —OPO(R′)₂; and each occurrence of R is independentlyhydrogen or an optionally substituted C₁₋₆ aliphatic group; and eachoccurrence of R′ is independently hydrogen or an optionally substitutedC₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated,or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-12membered saturated, partially unsaturated, or fully unsaturated bicyclicring system having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrencesof R′, are taken together with the atom(s) to which they are bound toform an optionally substituted 3-12 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur;provided that: a. when R¹ and R², taken together with the nitrogen atomto which they are bound, form an optionally substituted 4-memberedmonocyclic saturated or partially unsaturated ring having 0-3 additionalheteroatoms independently selected from nitrogen, sulfur, or oxygen;then 2-Oxazolidinone,3-[(3R,4R)-2-oxo-1-(2-phenyl-4-quinazolinyl)-4-[2-(3-pyridinyl)ethenyl]-3-azetidinyl]-4-phenyl-,(4S)— is excluded; b. when R¹ and R², taken together with the nitrogenatom to which they are bound, form an optionally substituted 5-memberedmonocyclic saturated or partially unsaturated ring having 0-3 additionalheteroatoms independently selected from nitrogen, sulfur, or oxygen;then: i. ring A is not optionally substitutedhexahydro-1H-1,4-diazepin-1-yl; and ii. Benzenesulfonamide,2-methoxy-5-[2-[[1-(2-phenyl-4-quinazolinyl)-3-pyrrolidinyl]amino]ethyl]-,(R) —, bis(trifluoroacetate), and Benzenesulfonamide,2-methoxy-5-[2-[[1-(2-phenyl-4-quinazolinyl)-3-pyrrolidinyl]amino]ethyl]-,(S)—, bis(trifluoroacetate) are excluded; iii. 3-Pyrrolidinamine,1-(2-phenyl-4-quinazolinyl)-, and (R)-3-Pyrrolidinamine,1-(2-phenyl-4-quinazolinyl)-, (S)— are excluded; iv. when R¹ and R²,taken together are unsubstituted pyrrolidin-1-yl, ring A isunsubstituted phenyl, and x is 1, then R³ is not 6-OMe or 6-OH; v. whenR¹ and R², taken together are unsubstituted pyrrolidin-1-yl, ring A isunsubstituted phenyl, and x is 2, then the two R³ groups are not 6-OMeand 7-OMe; vi. when R¹ and R², taken together are unsubstitutedpyrrolidin-1-yl, then ring A is not unsubstituted pyrrolidin-1-yl,optionally substituted piperazin-1-yl, unsubstituted morpholin-1-yl; orunsubstituted piperidin-1-yl; vii. when R¹ and R², taken together arepyrrolidin-1-yl, x is 0 and ring A is unsubstituted phenyl, then thepyrrolidin-1-yl group is not substituted at the 3-position with —OH or2-methoxy-phenoxy; viii. when R¹ and R², taken together areunsubstituted pyrrolidin-1-yl, and x is 0, then ring A is not 2,3-xylyl,3-methylphenyl, unsubstituted phenyl, 4-bromo-phenyl, 4-chloro-phenyl,3-nitro-phenyl, unsubstituted pyrid-3-yl, 2,4-dichlorophenyl,3,4-dichlorophenyl, 4-propoxyphenyl, 3-methylphenyl,3,4,5-trimethoxyphenyl, 2-chlorophenyl, unsubstituted pyrid-4-yl,2-hydroxyphenyl, or 4-(1,1-dimethylethyl)phenyl; c. when R¹ and R²,taken together with the nitrogen atom to which they are bound, form anoptionally substituted 6-membered monocyclic or bicyclic saturated orpartially unsaturated ring having 0-3 additional heteroatomsindependently selected from nitrogen, sulfur, or oxygen; then: i. whenR¹ and R², taken together form an unsubstituted morpholino ring, andring A is unsubstituted phenyl, then x is not 0, or if x is 1 or 2, thenR³ is not: 6-fluoro, 6,7-dimethoxy, 6-nitro, 6-AcHN—, 6-methox, 6-NH2,6-OCHN—, 6-OH, 6-AcMeN—, 6-TsHN—, 6-Me2N—, 7-OH, 6-amino-thiazol-2-yl,6-NHCOCOOEt, or 6-(4-phenyl-amino-thiazol-2-yl); ii. when R¹ and R²,taken together form an unsubstituted morpholino ring, and ring A isunsubstituted cyclohexyl, unsubstituted pyrid-3-yl, unsubstituted2-furyl, 2-fluorophenyl, 3-thienyl, benzofuran, pyridazine, phenylsubstituted in one or more of the 3, 4, or 5-position of the phenylring, and x is 1 or 2, then R³ is not 6-NH2, 6-OHCHN—, 6-OH, 7-OH,6-MsHN—, 6-AcHN—, 6-fluoro, or 6-OMe; iii. when R¹ and R², takentogether, form a piperid-4-one, piperid-4-ol, or thiomorpholino, or adimethyl substituted morpholino ring, ring A is unsubstituted phenyl,and x is 1, then R³ is not 6-OH; iv. when x is 0 and A is unsubstitutedphenyl, 3,4,5-trimethoxyphenyl, or 3,4-dimethoxyphenyl, then R¹ and R²,taken together is not optionally substituted piperidinyl or optionallysubstituted piperazinyl; v. when x is 2 or 3, and R³ is 6,7-diOMe, or6,7,8-triOMe, then R¹ and R², taken together is not optionallysubstituted piperidin-1-yl, piperazin-1-yl, or morpholin-1-yl; vi. whenx is 0 and ring A is unsubstituted phenyl, then R¹ and R₂, takentogether is not optionally substituted or fused piperazinyl; vii. when xis 0 and ring A is phenyl optionally substituted in one or more of the3-, 4-, or 5-positions of the phenyl ring, then R¹ and R², takentogether is not optionally substituted piperazin-1-yl, ormorpholin-1-yl; viii. when x is 0 and ring A is 2-F-phenyl, then R¹ andR², taken together is not 4-(2-Cl-phenyl)-piperazin-1-yl,4-(3-Cl-phenyl)-piperazin-1-yl, or unsubstituted morpholin-1-yl; ix.when x is 0 and ring A is 2-Cl-phenyl, then R¹ and R², taken together isnot unsubstituted morpholin-1-yl, 4-Me-piperazin-1-yl,4-Et-piperazin-1-yl, 4-phenyl-piperazin-1-yl, or4-CH₂Ph₂-piperazin-1-yl; x. when x is 0 and ring A is 2-OH-phenyl, thenR1 and R2, taken together is not unsubstituted morpholin-1-yl,4-(2-OMe-phenyl)-piperazin-1-yl, 4-CH2Ph-piperazin-1-yl,4-Et-piperazin-1-yl, or 4-Me-piperazin-1-yl; xi. when x is 0, x is 1 andR³ is 6-Br, or x is 2 and R³ is 6-7-diOMe, and ring A is optionallysubstituted 2- or 3-thienyl, then R¹ and R², taken together is not4-Ph-piperazin-1-yl, 4-(3-CF₃-phenyl)-piperazin-1-yl,4-(2-OEt-phenyl)-piperazin-1-yl, 4-Me-piperazinyl, or unsubstitutedmorpholin-1-yl; xii when x is 0, and ring A is unsubstituted pyrid-3-ylor pyrid-4-yl, then R¹ and R², taken together is not optionallysubstituted morpholin-1-yl, or optionally substituted piperazin-1-yl;xiii. when x is 0, and ring A is optionally substituted 1H-imidazol-2-ylor 1H-imidazol-1-yl, then R¹ and R² taken together is not unsubstitutedmorpholin-1-yl, 4-Me-piperazin-1-yl, or 4-CH₂CH₂OH-piperazin-1-yl; xiv.when x is 0 and ring A is 5-NO₂-thiazol-2-yl, then R¹ and R², takentogether is not 4-Me-piperazin-1-yl; xv. when x is 0 and ring A is5-NO₂-2-furanyl, then R¹ and R², taken together is not4-CH₂CH₂OH-piperazin-1-yl, 4-Me-piperazin-1-yl, or unsubstitutedmorpholin-1-yl; xvi. when x is 1, R³ is 6-OH and ring A is unsubstitutedphenyl, then R¹ and R², taken together is not unsubstitutedmorpholin-1-yl, or 4-Me-piperazin-1-yl; xvii. when x is 0 and R¹ and R²,taken together is unsubstituted piperidinyl, then ring A is not2-OH-phenyl, 4-OMe-phenyl, 4-F-phenyl, 4-NO₂-phenyl, pyrid-3-yl,pyrid-4-yl, 2-Cl-phenyl, 4-O_(n)Pr-phenyl, 3,4-dichlorophenyl,2-F-phenyl, 4-Br-phenyl, 4-Cl-phenyl, 3-NO₂-phenyl, or2,4-dichlorophenyl; xviii. when x is 0, ring A is 4-Br-phenyl,2-F-phenyl, 2-Cl-phenyl, 4-Cl-phenyl, 4-OnPr-phenyl, 2,4-dichlorophenyl,3,4-dichlorophenyl, 4-Me-phenyl, 3-Me-phenyl, pyrid-3-yl, pyrid-4-yl,2-OH-phenyl, 4-NO2-phenyl, 4-tBu-phenyl, then R¹ and R², taken togetheris not 2-Me-piperidin-1-yl, 4-CH2-Ph-piperidin-1-yl,4-Me-piperidin-1-yl, 3-COOEt-piperidin-1-yl, 4-COOEt-piperidin-1-yl,2-Et-piperidin-1-yl, 3-Me-piperidin-1-yl, 3,5-diMe-piperidin-1-yl,4-CONH₂-piperidin-1-yl, (4-piperidinyl, 4-carboxamide)-piperidin-1-yl,1,4-dioxa-8-azaspiro[4.5]decane, 3,4-dihydro-2(1H)-isoquinolinyl, orpiperidin-4-one; xix. when x is 1, R³ is 6-Br, 6-Cl, 6-OH, 6-OMe, or6-Me and ring A is 4-bromophenyl, 4-CH₂P(O)(OH)(OEt)phenyl, orunsubstituted phenyl, then R¹ and R², taken together, is not optionallysubstituted piperidinyl; xx. when x is 2, and R³ is 6,7-dimethoxy, and Ais unsubstituted phenyl, then R¹ and R², taken together is not1,4-dioxa-8-azaspiro[4.5]decane or 3,4-dihydro-2(1H)-isoquinolinyl; xxi.when x is 3, and the three occurrences of R³ are 5-OAc, 6-OAc, and8-piperidinyl, and ring A is unsubstituted phenyl, then R¹ and R², takentogether is not an unsubstituted piperidinyl ring; xxii. when x is 3 andthe three occurrences of R³ are 6-Me, 7-COOEt, and 8-Me, and ring A is2-Cl-phenyl, then R¹ and R², taken together, is not4-phenyl-piperidin-1-yl, 4-(4-Cl-phenyl)-piperazin-1-yl, unsubstitutedpiperazin-1-yl, 4-CH₂Ph-piperazin-1-yl, 4(2-Cl-phenyl)piperazin-1-yl, or4-COOEt-piperazin-1-yl; c. when R¹ and R², taken together with thenitrogen atom to which they are bound, form an optionally substituted7-membered monocyclic or bicyclic saturated or partially unsaturatedring having 0-3 additional heteroatoms independently selected fromnitrogen, sulfur, or oxygen; then: i. Benzenesulfonamide,2-methoxy-5-[2-[5-(2-phenyl-4-quinazolinyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethyl]-,and bis(trifluoroacetate) 2,5-Diazabicyclo[2.2.1]heptane,2-(2-phenyl-4-quinazolinyl)- are excluded; ii. when x is 2 and bothoccurrences of R³ are OMe, and ring A is 4-Cl-phenyl, then R¹ and R²,taken together is not unsubstituted hexahydro-1H-azepin-1-yl; iii. whenx is 0 and R¹ and R², taken together is unsubstitutedhexahydro-1H-azepin-1-yl, then ring A is not unsubstituted phenyl,4-F-phenyl, 4-NO₂-phenyl, pyrid-4-yl, 3,4-diCl-phenyl, 2-Cl-phenyl,2,4-diCl-phenyl, 2,4-diCl-phenyl, 3-NO₂-phenyl, 4-Cl-phenyl,4-O_(n)Pr-phenyl, 3-Me-phenyl, 3,4-OMe-phenyl, 3,4,5-OMe-phenyl,pyrid-3-yl, or 2-OH-phenyl; d. when R¹ and R², taken together with thenitrogen atom to which they are bound, form an optionally substituted8-membered monocyclic or bicyclic saturated or partially unsaturatedring having 0-3 additional heteroatoms independently selected fromnitrogen, sulfur, or oxygen; then: i. Benzenesulfonamide,2-methoxy-5-[2-[8-(2-phenyl-4-quinazolinyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethyl]-,bis(trifluoroacetate) 3,8-Diazabicyclo[3.2.1]octane,3-(phenylmethyl)-8-(2-phenyl-4-quinazolinyl)-3,8-Diazabicyclo[3.2.1]octane,8-(2-phenyl-4-quinazolinyl)-; Quinazoline,2-(3-methylphenyl)-4-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)-,monohydrochloride; Quinazoline,2-(4-nitrophenyl)-4-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)-,monohydrochloride; Quinazoline,2-(3-methylphenyl)-4-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)-;Quinazoline,2-(4-methylphenyl)-4-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)-; andQuinazoline,2-(4-nitrophenyl)-4-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)- areexcluded; and e. when R¹ and R², taken together with the nitrogen atomto which they are bound, form an optionally substituted 9-memberedmonocyclic or bicyclic saturated or partially unsaturated ring having0-3 additional heteroatoms independently selected from nitrogen, sulfur,or oxygen; then: Piperazine,1-[4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-6,7-dimethoxy-2-quinazolinyl]-4-(2-furanylcarbonyl)-is excluded.
 2. The compound of claim 1, wherein the ring formed by R¹and R² taken together is selected from:

wherein the ring formed by R¹ and R² taken together, is optionallysubstituted at one or more substitutable carbon, nitrogen, or sulfuratoms with z independent occurrences of —R⁴, and z is 0-5.
 3. Thecompound of claim 2, wherein R¹ and R² taken together is an optionallysubstituted ring selected from azetidin-1-yl (jj), pyrrolidin-1-yl (ff),piperidin1-yl (dd), piperazin-1-yl (cc), or morpholin-4-yl (ee).
 4. Thecompound of claim 2, wherein R¹ and R² taken together is an optionallysubstituted ring selected from azetidin-1-yl (jj), pyrrolidin-1-yl (ff),piperidin1-yl (dd), or piperazin-1-yl (cc).
 5. The compound of claim 2,wherein R¹ and R², taken together is selected from: a. optionallysubstituted azetidin-1-yl (jj), wherein z is 1 or 2 and at least oneoccurrence of R⁴ is —NRSO₂R′, —NRCOOR′, or —NRCOR′; b. optionallysubstituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRSO₂R′; c.optionally substituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is—NRCOOR′; d. optionally substituted azetidin-1-yl (jj), wherein z is 1and R⁴ is —NRCOR′; e. optionally substituted pyrrolidin-1-yl (ff),wherein z is 1 or 2 and R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or—CH₂OR′; f. optionally substituted piperidin-1-yl (dd), wherein z is 1or 2 and at least one occurrence of R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃,—OR′, or —CH₂OR′, —NRSO₂R′, —NRCOOR′, or —OCON(R′)₂; g. optionallysubstituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is F, CF₃, CH₃,—CH₂CH₃, —OR′, or —CH₂OR′; h. optionally substituted piperidin-1-yl(dd), wherein z is 1 and R⁴ is —NRSO₂R′; i. optionally substitutedpiperidin-1-yl (dd), wherein z is 1 and R⁴ is —NRCOOR′; j. optionallysubstituted piperazin-1-yl (cc), wherein z is 1 or 2 and at least oneoccurrence of R⁴ is —SOR′, —CON(R′)₂, —SO₂N(R′)₂, —COR′, or —COOR′; k.optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is—SOR′ l. optionally substituted piperazin-1-yl (cc), wherein z is 1 andR⁴ is —COOR′; m. optionally substituted piperazin-1-yl (cc), wherein zis 1 and R⁴ is —CON(R′)₂; n. optionally substituted piperazin-1-yl (cc),wherein z is 1 and R⁴ is —SO₂N(R′)₂; or o. optionally substitutedpiperazin-1-yl (cc), wherein z is 1 and R⁴ is —COR′.
 6. The compound ofclaim 1, wherein z is 0-5, and R⁴ groups, when present, are eachindependently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′,—SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′,—SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected fromC₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic,arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆ alkyl, orheterocycloaliphaticC₁-C₆alkyl.
 7. The compound of claim 1, wherein z is0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃, —CH₂CH₃,CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃,—OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂,—SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂,—NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, oran optionally substituted group selected from -piperidinyl, piperizinyl,morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy,—CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl.
 8. The compoundof claim 1, wherein x is 0-4, and R³ groups, when present, are eachindependently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′,—SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′,—SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected fromC₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic,arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.
 9. The compound of claim 1, wherein x is1 or 2, and each occurrence of R³ is independently Cl, Br, F, CF₃,—OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂,—O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃,—NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or anoptionally substituted group selected from -piperidinyl, piperizinyl,morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.
 10. The compound ofclaim 1, wherein x is 1 or 2 and each R³ group is independently halogen,CN, optionally substituted C₁-C₆alkyl, OR′, N(R′)₂, CON(R′)₂, or NRCOR′.11. The compound of claim 1, wherein x is 1 or 2, and each R³ group is—Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.
 12. The compound ofclaim 1, wherein x is 1 and R³ is at the 6-position of the quinazolinering and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.
 13. The compound ofclaim 1, wherein x is 1 and R³ is at the 7-position of the quinazolinering and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.
 15. The compound ofclaim 1, wherein x is 1 and R³ is at the 6-position of the quinazolinering and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. 15.The compound of claim 1, wherein x is 1 and R³ is at the 7-position ofthe quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃,or —OCH₂CH₃.
 16. The compound of claim 1, wherein x is 1 and R³ is atthe 6-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′. 17.The compound of claim 1, wherein x is 1 and R³ is at the 7-position ofthe quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃,or —OCH₂CH₃.
 18. The compound of claim 1, wherein ring A is a groupselected from:


19. The compound of claim 17, wherein ring A is optionally substitutedphenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, or pyrrol-1-yl.
 20. Thecompound of claim 1, wherein y is 0-5, q is 0-2, and R⁵ and R^(5a)groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂,—CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂,—S(O)₂N(R′)₂, —OCOR′, —COR′, —CO₂R′, —OCON(R′)₂, —NR′SO₂R′,—OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, —OPO(R′)₂,or an optionally substituted group selected from C₁₋C₆aliphatic, aryl,heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆ alkyl, orheterocycloaliphaticC₁-C₆alkyl.
 21. The compound of claim 1, wherein yis 0-5, and q is 1 or 2, and each occurrence of R^(5a) is independentlyCl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂,—O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃,—SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂,4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), —COCH₃, optionallysubstituted phenoxy, or optionally substituted benzyloxy.
 22. Thecompound of claim 1, wherein: a. y is 0, and q is 1 and R^(5a) is F; b.y is 0, q is 1, and R^(5a) is OR′; c. y is 0, q is 1 and R^(5a) is OH;d. y is 0, q is 2 and one occurrence of R^(5a) is OR′ and the otheroccurrence of R^(5a) is F; or e. y is 0, q is 2 and one occurrence ofR^(5a) is OH and the other occurrence of R^(5a) is F.
 23. The compoundof claim 1, wherein ring A is optionally substituted phenyl andcompounds have the structure IA-i:

wherein: y is 0-5; q is 0-2; and each occurrence of R^(5a) isindependently an optionally substituted C₁-C₆aliphatic group, halogen,—OR′, —SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′,—OCOR′, —CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′,—NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂,—OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂.
 24. The compound of claim23, wherein the ring formed by R¹ and R² taken together is selected from

wherein the ring formed by R¹ and R² taken together, is optionallysubstituted at one or more substitutable carbon, nitrogen, or sulfuratoms with z independent occurrences of —R⁴, and z is 0-5.
 25. Thecompound of claim 24, wherein R¹ and R² taken together is an optionallysubstituted ring selected from azetidin-1-yl (jj), pyrrolidin-1-yl (ff),piperidin1-yl (dd), piperazin-1-yl (cc), or morpholin-4-yl (ee).
 26. Thecompound of claim 24, wherein R¹ and R² taken together is an optionallysubstituted ring selected from azetidin-1-yl (jj), pyrrolidin-1-yl (ff),piperidin1-yl (dd), or piperazin-1-yl (cc).
 27. The compound of claim23, wherein z is 0-5, and R⁴ groups, when present, are eachindependently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′,—SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′,—SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected fromC₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic,arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆ alkyl, orheterocycloaliphaticC₁-C₆alkyl.
 28. The compound of claim 23, wherein zis 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃,—CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂,—COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂,—SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂,—NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, oran optionally substituted group selected from -piperidinyl, piperizinyl,morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy,—CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl.
 29. The compoundof claim 23, wherein R¹ and R², taken together is selected from: a.optionally substituted azetidin-1-yl (jj), wherein z is 1 or 2 and atleast one occurrence of R⁴ is —NRSO₂R′, —NRCOOR′, or —NRCOR′; b.optionally substituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is—NRSO₂R′; c. optionally substituted azetidin-1-yl (jj), wherein z is 1and R⁴ is —NRCOOR′; d. optionally substituted azetidin-1-yl (jj),wherein z is 1 and R⁴ is —NRCOR′; e. optionally substitutedpyrrolidin-1-yl (ff), wherein z is 1 or 2 and R⁴ is Cl, Br, F, CF₃, CH₃,—CH₂CH₃, —OR′, or —CH₂OR′; f. optionally substituted piperidin-1-yl(dd), wherein z is 1 or 2 and at least one occurrence of R⁴ is Cl, Br,F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′, —NRSO₂R′, —NRCOOR′, or—OCON(R′)₂; g. optionally substituted piperidin-1-yl (dd), wherein z is1 and R⁴ is F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′; h. optionallysubstituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is —NRSO₂R′; i.optionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is—NRCOOR′; j. optionally substituted piperazin-1-yl (cc), wherein z is 1or 2 and at least one occurrence of R⁴ is —SOR′, —CON(R′)₂, —SO₂N(R′)₂,—COR′, or —COOR′; k. optionally substituted piperazin-1-yl (cc), whereinz is 1 and R⁴ is —SOR′ l. optionally substituted piperazin-1-yl (cc),wherein z is 1 and R⁴ is —COOR′; m. optionally substitutedpiperazin-1-yl (cc), wherein z is 1 and R⁴ is —CON(R′)₂; n. optionallysubstituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —SO₂N(R′)₂; oro. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is—COR′.
 30. The compound of claim 23, wherein x is 0-4, and R³ groups,when present, are each independently halogen, CN, NO₂, —N(R′)₂,—CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂,—OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionallysubstituted group selected from C₁₋C₆aliphatic, aryl, heteroaryl,cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.
 31. The compound of claim 23, wherein xis 1 or 2, and each occurrence of R³ is independently Cl, Br, F, CF₃,—OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂,—O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃,—NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or anoptionally substituted group selected from -piperidinyl, piperizinyl,morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.
 32. The compound ofclaim 23 wherein x is 1 or 2 and each R³ group is independently halogen,CN, optionally substituted C₁-C₆alkyl, OR′, N(R′)₂, CON(R′)₂, or NRCOR′.33. The compound of claim 23, wherein x is 1 or 2, and each R³ group is—Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.
 34. The compound ofclaim 23, wherein x is 1 and R³ is at the 6-position of the quinazolinering and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.
 35. The compound ofclaim 23, wherein x is 1 and R³ is at the 7-position of the quinazolinering and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.
 36. The compound ofclaim 23, wherein x is 1 and R³ is at the 6-position of the quinazolinering and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. 37.The compound of claim 23, wherein x is 1 and R³ is at the 7-position ofthe quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃,or —OCH₂CH₃.
 38. The compound of claim 23, wherein x is 1 and R³ is atthe 6-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′. 39.The compound of claim 23, wherein x is 1 and R³ is at the 7-position ofthe quinazoline ring and is —CON(R′)₂, or NRCOR′.
 40. The compound ofclaim 23, wherein y is 0-5, q is 0-2, and R⁵ and R^(5a) groups, whenpresent, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂,—OR′, —CH₂OR′, —SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂, —S(O)₂N(R′)₂, —OCOR′,—COR′, —CO₂R′, —OCON(R′)₂, —NR′SO₂R′, —OP(O)(OR′)₂, —P(O)(OR′)₂,—OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, —OPO(R′)₂, or an optionally substitutedgroup selected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic,heterocycloaliphatic, arylC₁-C₁₋₆alkyl, heteroarylC₁-C₆alkyl,cycloaliphaticC₁-C₆ alkyl, or heterocycloaliphaticC₁-C₁₋₆alkyl.
 41. Thecompound of claim 23, wherein y is 0-5, and q is 1 or 2, and eachoccurrence of R^(5a) is independently Cl, Br, F, CF₃, Me, Et, CN, —COOH,—NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH,—OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃,—OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂,OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionallysubstituted benzyloxy.
 42. The compound of claim 23, wherein: f. y is 0,and q is 1 and R^(5a) is F substituted at the 2-position of the phenylring; g. y is 0, q is 1, and R^(5a) is OR′ substituted at the 2-positionof the phenyl ring; h. y is 0, q is 1 and R^(5a) is OH substituted atthe 2-position of the phenyl ring; i. y is 0, q is 2 and one occurrenceof R^(5a) is OR′ substituted at the 2-position of the phenyl ring andthe other occurrence of R^(5a) is F substituted at the 6-position of thephenyl ring; or j. y is 0, q is 2 and one occurrence of R^(5a) is OHsubstituted at the 2-position of the phenyl ring, and the otheroccurrence of R^(5a) is F substituted at the 6-position of the phenylring.
 43. The compound of claim 23, wherein q is 1 and R^(5a) is at the2-position of the phenyl ring, and compounds have the structure IA-ii:

wherein: a) the ring formed by R¹ and R² taken together is selectedfrom:

and the ring formed by R¹ and R² taken together, is optionallysubstituted at one or more substitutable carbon, nitrogen, or sulfuratoms with z independent occurrences of —R⁴, and z is 0-5, b) wherein zis 0-5, and R⁴ groups, when present, are each independently halogen, CN,NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′,—CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or anoptionally substituted group selected from C₁₋C₆aliphatic, aryl,heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆ alkyl. c) wherein x is 0-4, and R³ groups,when present, are each independently halogen, CN, NO₂, —N(R′)₂,—CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂,—OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionallysubstituted group selected from C₁₋C₆aliphatic, aryl, heteroaryl,cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆ alkyl. d) wherein y is 0-5, and R⁵ groups,when present, are each independently halogen, CN, NO₂, —N(R′)₂,—CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂,—S(O)₂N(R′)₂, —OCOR′, —COR′, —CO₂R′, —OCON(R′)₂, —NR′SO₂R′,—OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, —OPO(R′)₂,or an optionally substituted group selected from C₁₋C₆aliphatic, aryl,heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆ alkyl, cycloaliphaticC₁-C₆ alkyl, orheterocycloaliphaticC₁-C₆ alkyl; and e) R^(5a) is Cl, Br, F, CF₃, Me,Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂,—COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂,—OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl,OCOCH(CH₃)₂, OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy,or optionally substituted benzyloxy.
 44. The compound of claim 23,wherein q is 1 and R^(5a) is at the 2-position of the phenyl ring, andcompounds have the structure IA-ii:

wherein: a) R¹ and R² taken together is an optionally substituted ringselected from azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidin1-yl(dd), or piperazin-1-yl (cc); b) z is 0-5 and R⁴ groups are eachindependently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂,—N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃,—SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃,—C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃,—COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionallysubstituted group selected from -piperidinyl, piperizinyl, morpholino,C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl,pyridyl, —CH₂pyridyl, or —CH₂thiazolyl; c) x is 1 or 2, and eachoccurrence of R³ is independently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN,—COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃,—OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂,—CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substitutedgroup selected from -piperidinyl, piperizinyl, morpholino, phenyl,phenyloxy, benzyl, or benzyloxy; d) wherein y is 0-4, and R⁵ groups,when present, are each independently Cl, Br, F, CF₃, Me, Et, CN, —COOH,—NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH,—OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃,—OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂,OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionallysubstituted benzyloxy; and e) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃,—OCH₂CH₃, —CH₂OH, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃,—O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or—COCH₃.
 45. The compound of claim 44, wherein x is 1 and R³ is at the6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃,or —CN.
 46. The compound of claim 44, wherein x is 1 and R³ is at the7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃,or —CN.
 47. The compound of claim 44, wherein x is 1 and R³ is at the6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —OCH₃, or —OCH₂CH₃.
 48. The compound of claim 44 wherein x is 1and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃,—CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.
 49. The compound of claim44, wherein x is 1 and R³ is at the 6-position of the quinazoline ringand is —CON(R′)₂, or NRCOR′.
 50. The compound of claim 44, wherein x is1 and R³ is at the 7-position of the quinazoline ring and is —CON(R′)₂,or NRCOR′.
 51. The compound of claim 44, wherein R^(5a) is Cl, F, CF₃,Me, Et, —OH, OR′, —OCH₃, —OCH₂CH₃.
 52. The compound of claim 44, whereinR^(5a) is OR′.
 53. The compound of claim 44, wherein R^(5a) is OH. 54.The compound of claim 44, wherein R^(5a) is F.
 55. The compound of claim23, wherein q is 1 and R^(5a) is at the 2-position of the phenyl ring,and compounds have the structure IA-ii:

wherein: a) R¹ and R² taken together is an optionally substituted ringselected from azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidin1-yl(dd), or piperazin-1-yl (cc); b) z is 0-5 and R⁴ groups are eachindependently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂,—N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃,—SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃,—C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃,—COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionallysubstituted group selected from -piperidinyl, piperizinyl, morpholino,C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl,pyridyl, —CH₂pyridyl, or —CH₂thiazolyl; c) x is 1, and each occurrenceof R³ is independently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —OH, or—OCH₃; d) y is 0 or 1, and R⁵ groups, when present, are eachindependently Cl, Br, F, CF₃, Me, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH,—NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂; and e) R^(5a) is F, —OR′, or NHSO₂R′.56. The compound of claim 55, wherein x is 1 and R³ is at the 6-positionof the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃,—CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or—CN.
 57. The compound of claim 55, wherein x is 1 and R³ is at the7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃,or —CN.
 58. The compound of claim 55, wherein x is 1 and R³ is at the6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —OCH₃, or —OCH₂CH₃.
 59. The compound of claim 55, wherein x is 1and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃,—CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.
 60. The compound of claim55, wherein x is 1 and R³ is at the 6-position of the quinazoline ringand is —CON(R′)₂, or NRCOR′.
 61. The compound of claim 55, wherein x is1 and R³ is at the 7-position of the quinazoline ring and is —CON(R′)₂,or NRCOR′.
 62. The compound of claim 55, wherein R^(5a) is OR′ and x is1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃,—CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.
 63. The compound of claim55, wherein R^(5a) is OR′ and x is 1 and R³ is at the 7-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or—OCH₂CH₃
 64. The compound of claim 55, wherein R¹ and R², taken togetheris selected from: a. optionally substituted azetidin-1-yl (jj), whereinz is 1 or 2 and at least one occurrence of R⁴ is —NRSO₂R′, —NRCOOR′, or—NRCOR′; b. optionally substituted azetidin-1-yl (jj), wherein z is 1and R⁴ is —NRSO₂R′; c. optionally substituted azetidin-1-yl (jj),wherein z is 1 and R⁴ is —NRCOOR′; d. optionally substitutedazetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRCOR′; e. optionallysubstituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R⁴ is Cl, Br,F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′; f. optionally substitutedpiperidin-1-yl (dd), wherein z is 1 or 2 and at least one occurrence ofR⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′, —NRSO₂R′,—NRCOOR′, or —OCON(R′)₂; g. optionally substituted piperidin-1-yl (dd),wherein z is 1 and R⁴ is F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′; h.optionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is—NRSO₂R′; i. optionally substituted piperidin-1-yl (dd), wherein z is 1and R⁴ is —NRCOOR′; j. optionally substituted piperazin-1-yl (cc),wherein z is 1 or 2 and at least one occurrence of R⁴ is —SOR′,—CON(R′)₂, —SO₂N(R′)₂, —COR′, or —COOR′; k. optionally substitutedpiperazin-1-yl (cc), wherein z is 1 and R⁴ is —SOR′ l. optionallysubstituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —COOR′; m.optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is—CON(R′)₂; n. optionally substituted piperazin-1-yl (cc), wherein z is 1and R⁴ is —SO₂N(R′)₂; or o. optionally substituted piperazin-1-yl (cc),wherein z is 1 and R⁴ is —COR′.
 65. A compound of formula IA-ii:

wherein R¹ and R² are each independently an optionally substituted groupselected from C₁₋₆aliphatic, Cy¹, wherein Cy¹ is a 5-7-memberedmonocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, oris a 3-12-membered saturated or partially unsaturated monocyclic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, wherein Cy¹ is bonded directly to the nitrogen atom or is bondedthrough an optionally substituted C₁₋₄aliphatic group, wherein one ormore methylene units in the C₁₋₄aliphatic group are optionally replacedwith —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—;wherein R¹ and R², are each optionally and independently substituted atone or more substitutable carbon, nitrogen, or sulfur atoms with zindependent occurrences of —R⁴, wherein z is 0-5; x is 0-4; y is 0-4;each occurrence of R³, R⁴, and R⁵ is independently Q-R^(X); wherein Q isa bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacentmethylene units of Q are optionally and independently replaced by —NR—,—S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—,—SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—,—SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of R^(X)is independently selected from —R′, ═O, ═NR′, halogen, —NO₂, —CN, —OR′,—SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′,—CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′,—NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂,—OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂; R^(5a) is an optionallysubstituted C₁-C₆aliphatic group, halogen, —OR′, —SR′, —N(R′)₂,—NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂,—OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂,—COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′,—PO(R′)₂, or —OPO(R′)₂; and each occurrence of R is independentlyhydrogen or an optionally substituted C₁₋₆ aliphatic group; and eachoccurrence of R′ is independently hydrogen or an optionally substitutedC₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated,or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-12membered saturated, partially unsaturated, or fully unsaturated bicyclicring system having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrencesof R′, are taken together with the atom(s) to which they are bound toform an optionally substituted 3-12 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur;provided that: a. when x is 0, R¹ is hydrogen, and R^(5a) is Cl, Me,CF₃, Br, or F, then R² is not —(CH₂)₂-4-Cy¹, —SO₂CH₂Cy¹, or —CH₂SO₂Cy¹,wherein Cy¹ is a 5-7-membered monocyclic aryl ring or an 8-10-memberedbicyclic aryl ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or is a 3-8-membered saturated or partiallyunsaturated monocyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; b. when x is 0, and R^(5a) isCl, Me, NO₂, or OH, then: i. when R¹ is hydrogen, R² is not Me, iBu,nBu, —COCH₃, —CH₂COOEt, —CH₂COOMe, —CH₂CH₂OH, iPr, —CH₂-pyridyl, —CH₂Ph,—(CH₂)₃NH₂, —(CH₂)₂-moropholinyl, or —CH₂CH₂Ph; ii. R¹ and R² are notsimultaneously Et or Me; and iii. when R¹ is Et, then R² is not4-Me-phenyl, 4-OMe-phenyl, or 2-Me-phenyl; c. when x is 1 and R³ is6-Cl, or 7-F, or x is 0 and R^(5a) is —OPr_(n) or Cl, then when R¹ ishydrogen, R² is not —(CH₂)₂-morpholino, or —CH₂(benzofuran); and d. whenx is 2 and one occurrence of R³ is 6-OMe and the other occurrence of R³is 7-OMe, and R^(5a) is F, then when R¹ is hydrogen, R² is not—(CH₂)₃N(CH₃)₂;
 66. The compound of claim 65, wherein a) one of R¹ or R²is hydrogen, and the other of R¹ and R² is selected from: i) Cy¹ whereinCy¹ is bonded directly to the nitrogen atom or is bonded through anoptionally substituted C₁₋₄aliphatic group, wherein one or moremethylene units in the C₁₋₄aliphatic group are optionally replaced with—NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or ii) anoptionally substituted C₁₋₄aliphatic group, wherein one or moremethylene units in the C₁₋₄aliphatic group are optionally replaced with—NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or b) R¹and R² are each independently selected from Cy¹, wherein Cy¹ is bondeddirectly to the nitrogen atom or is bonded through an optionallysubstituted C₁₋₄aliphatic group, wherein one or more methylene units inthe C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or an optionally substitutedC₁₋₄aliphatic group, wherein one or more methylene units in theC₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO—,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—.
 67. The compound of claim65, wherein Cy¹ is:


68. The compound of claim 65, wherein R¹ is hydrogen or an optionallysubstituted C₁-C₄aliphatic group and R² is —CHR-Cy¹, wherein R ishydrogen or C₁-C₄alkyl, and Cy¹ is:


69. The compound of claim 65, wherein R¹ and R² groups are eachindependently an optionally substituted C₁₋₄aliphatic group and are eachindependently selected from optionally substituted methyl, ethyl,cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH₂CH₃, (CH₂)₂OCH₃,CH₂CO)OCH₂CH₃, CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, or n-butyl.
 70. The compoundof claim 65, wherein z is 0-5, and R⁴ groups, when present, are eachindependently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′,—SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′,—SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected fromC₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic,arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆ alkyl, orheterocycloaliphaticC₁-C₆alkyl.
 71. The compound of claim 65, wherein zis 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃,—CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂,—COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂,—SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂,—NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, oran optionally substituted group selected from -piperidinyl, piperizinyl,morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy,—CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl.
 72. The compoundof claim 65, wherein x is 0-4, and R³ groups, when present, are eachindependently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′,—SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′,—SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected fromC₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic,arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.
 73. The compound of claim 65, wherein xis 1 or 2, and each occurrence of R³ is independently Cl, Br, F, CF₃,—OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂,—O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃,—NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or anoptionally substituted group selected from -piperidinyl, piperizinyl,morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.
 74. The compound ofclaim 65, wherein x is 1 or 2 and each R³ group is independentlyhalogen, CN, optionally substituted C₁-C₆alkyl, OR′, N(R′)₂, CON(R′)₂,or NRCOR′.
 75. The compound of claim 65, wherein x is 1 or 2, and eachR³ group is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.
 75. The compound ofclaim 65, wherein x is 1 and R³ is at the 6-position of the quinazolinering and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.
 76. The compound ofclaim 65, wherein x is 1 and R³ is at the 7-position of the quinazolinering and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.
 77. The compound ofclaim 65, wherein x is 1 and R³ is at the 6-position of the quinazolinering and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. 78.The compound of claim 65, wherein x is 1 and R³ is at the 7-position ofthe quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃,or —OCH₂CH₃.
 79. The compound of claim 65, wherein x is 1 and R³ is atthe 6-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′. 80.The compound of claim 65, wherein x is 1 and R³ is at the 7-position ofthe quinazoline ring and is —CON(R′)₂, or NRCOR′.
 81. The compound ofclaim 65, wherein y is 0-4, q is 0-2, and R⁵ and R^(5a) groups, whenpresent, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂,—OR′, —CH₂OR′, —SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂, —S(O)₂N(R′)₂, —OCOR′,—COR′, —CO₂R′, —OCON(R′)₂, —NR′SO₂R′, —OP(O)(OR′)₂, —P(O)(OR′)₂,—OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, —OPO(R′)₂, or an optionally substitutedgroup selected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic,heterocycloaliphatic, arylC₁-C₁₋₆alkyl, heteroarylC₁-C₆alkyl,cycloaliphaticC₁-C₆ alkyl, or heterocycloaliphaticC₁-C₁₋₆alkyl.
 82. Thecompound of claim 65, wherein y is 0-4, and q is 1 or 2, and eachoccurrence of R^(5a) is independently Cl, Br, F, CF₃, Me, Et, CN, —COOH,—NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH,—OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃,—OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂,OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionallysubstituted benzyloxy.
 83. The compound of claim 65, wherein: y is 0, qis 1, and R^(5a) is F; y is 0, q is 1, and R^(5a) is OR′; y is 0, q is 1and R^(5a) is OH; y is 1, R^(5a) is OR′ and R⁵ is F, wherein OR′ issubstituted at the 2-position of the phenyl ring and F is substituted atthe 6-position of the phenyl ring; or y is 1, R^(5a) is OH and R⁵ is F,wherein OH is substituted at the 2-position of the phenyl ring and F issubstituted at the 6-position of the phenyl ring.
 84. The compound ofclaim 65, wherein: a) one of R¹ or R² is hydrogen, and the other of R¹and R² is selected from Cy¹, wherein Cy¹ is bonded directly to thenitrogen atom or is bonded through an optionally substitutedC₁₋₄aliphatic group, wherein one or more methylene units in theC₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—,—NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—, or an optionally substitutedC₁₋₄aliphatic group, wherein one or more methylene units in theC₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—,—NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or R¹ and R² are each independentlyselected from an optionally substituted C₁₋₄aliphatic group, wherein oneor more methylene units in the C₁₋₄aliphatic group are optionallyreplaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or—NRSO₂—; or Cy¹ wherein Cy¹ is bonded to the nitrogen atom directly oris bonded through an optionally substituted C₁₋₄aliphatic group, whereinone or more methylene units in the C₁₋₄aliphatic group are optionallyreplaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or—NRSO₂—; b) z is 0-5 and R⁴ groups are each independently Cl, Br, F,CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃,—CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃,—SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂,—C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃,—C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted groupselected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl,phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or—CH₂thiazolyl; c) x is 0, 1, or 2, and each occurrence of R³ isindependently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂,—N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃,—CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃,—CONHCH₂CH₃, or an optionally substituted group selected from-piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, orbenzyloxy; d) wherein y is 0-4, and R⁵ groups, when present, are eachindependently Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂,—N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃,—CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃,—O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl),—COCH₃, optionally substituted phenoxy, or optionally substitutedbenzyloxy; and e) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃,—CH₂OH, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃,—O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or—COCH₃.
 85. The compound of claim 84, wherein x is 1 and R³ is at the6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃,or —CN.
 86. The compound of claim 84 wherein x is 1 and R³ is at the7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃,or —CN.
 87. The compound of claim 84, wherein x is 1 and R³ is at the6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —OCH₃, or —OCH₂CH₃.
 88. The compound of claim 84, wherein x is 1and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃,—CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.
 89. The compound of claim84, wherein x is 1 and R³ is at the 6-position of the quinazoline ringand is —CON(R′)₂, or NRCOR′.
 90. The compound of claim 84, wherein x is1 and R³ is at the 7-position of the quinazoline ring and is —CON(R′)₂,or NRCOR′.
 91. The compound of claim 84, wherein R^(5a) is Cl, F, CF₃,Me, Et, —OH, —OCH₃, —OCH₂CH₃.
 92. The compound of claim 84, wherein: yis 0, q is 1, and R^(5a) is F; y is 0, q is 1, and R^(5a) is OR′; y is0, q is 1 and R^(5a) is OH; y is 1, R^(5a) is OR′ and R⁵ is F, whereinOR′ is substituted at the 2-position of the phenyl ring and F issubstituted at the 6-position of the phenyl ring; or y is 1, R^(5a) isOH and R⁵ is F, wherein OH is substituted at the 2-position of thephenyl ring and F is substituted at the 6-position of the phenyl ring.93. The compound of claim 84, wherein: a): one of R¹ or R² is hydrogen,and the other of R¹ and R² is selected from Cy¹, wherein Cy¹ is bondeddirectly to the nitrogen atom or is bonded through an optionallysubstituted C₁₋₄aliphatic group, wherein one or more methylene units inthe C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—, or an optionally substitutedC₁₋₄aliphatic group, wherein one or more methylene units in theC₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—,—NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or R¹ and R² are each independentlyselected from an optionally substituted C₁₋₄aliphatic group, wherein oneor more methylene units in the C₁₋₄aliphatic group are optionallyreplaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or—NRSO₂—; or Cy¹ wherein Cy¹ is bonded to the nitrogen atom directly oris bonded through an optionally substituted C₁₋₄aliphatic group, whereinone or more methylene units in the C₁₋₄aliphatic group are optionallyreplaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or—NRSO₂—; and Cy¹ is selected from:

or R¹ and R² are each independently an optionally substitutedC₁₋₄aliphatic group and are each independently selected from optionallysubstituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl,(CO)OCH₂CH₃, (CH₂)₂OCH₃, CH₂CO)OCH₂CH₃, CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, orn-butyl; b) z is 0-5 and R⁴ groups are each independently Cl, Br, F,CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃,—CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃,—SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂,—C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃,—C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted groupselected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl,phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or—CH₂thiazolyl; c) x is 0, 1, or 2, and each occurrence of R³ isindependently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂,—N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃,—CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃,—CONHCH₂CH₃, or an optionally substituted group selected from-piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, orbenzyloxy; d) wherein y is 0-4, and R⁵ groups, when present, are eachindependently Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂,—N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃,—CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃,—O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl),—COCH₃, optionally substituted phenoxy, or optionally substitutedbenzyloxy; and e) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃,—CH₂OH, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃,—O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or—COCH₃.
 94. The compound of claim 93, wherein x is 1 and R³ is at the6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃,or —CN.
 95. The compound of claim 93 wherein x is 1 and R³ is at the7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃,or —CN.
 96. The compound of claim 93, wherein x is 1 and R³ is at the6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —OCH₃, or —OCH₂CH₃.
 97. The compound of claim 93, wherein x is 1and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃,—CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.
 98. The compound of claim93, wherein x is 1 and R³ is at the 6-position of the quinazoline ringand is —CON(R′)₂, or NRCOR′.
 99. The compound of claim 93, wherein x is1 and R³ is at the 7-position of the quinazoline ring and is —CON(R′)₂,or NRCOR′.
 100. The compound of claim 93, wherein R^(5a) is Cl, F, CF₃,Me, Et, —OH, —OCH₃, —OCH₂CH₃.
 101. The compound of claim 93, wherein: yis 0, q is 1, and R^(5a) is F; y is 0, q is 1, and R^(5a) is OR′; y is0, q is 1 and R^(5a) is OH; y is 1, R^(5a) is OR′ and R⁵ is F, whereinOR′ is substituted at the 2-position of the phenyl ring and F issubstituted at the 6-position of the phenyl ring; or y is 1, R^(5a) isOH and R⁵ is F, wherein OH is substituted at the 2-position of thephenyl ring and F is substituted at the 6-position of the phenyl ring.102. A compound of formula IA-i:

or a pharmaceutically acceptable salt thereof, wherein R¹ and R² areeach independently an optionally substituted group selected fromC₁₋₆aliphatic, Cy¹, wherein Cy¹ is a 5-7-membered monocyclic aryl ringor an 8-10-membered bicyclic aryl ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or is a3-12-membered saturated or partially unsaturated monocyclic ring having0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein Cy¹ is bonded directly to the nitrogen atom or is bonded throughan optionally substituted C₁₋₄aliphatic group, wherein one or moremethylene units in the C₁₋₄aliphatic group are optionally replaced with—NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; wherein R¹and R², are each optionally and independently substituted at one or moresubstitutable carbon, nitrogen, or sulfur atoms with z independentoccurrences of —R⁴, wherein z is 0-5; x is 1 and R³ is substituted ateither the 6- or 7-position of the quinazoline ring; y is 0-4; q is 0, 1or 2; each occurrence of R³, R⁴, and R⁵ is independently Q-R^(X);wherein Q is a bond or is a C₁-C₆ alkylidene chain wherein up to twonon-adjacent methylene units of Q are optionally and independentlyreplaced by —NR—, —S—, —O—, —CS—, —CO₂—, —COO, —CO—, —COCO—, —CONR—,—NRCO—, —NRCO₂—, —SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—,—NRSO₂NR—, —SO—, —SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and eachoccurrence of R^(X) is independently selected from —R′, ═O, ═NR′,halogen, —NO₂, —CN, —OR′, —SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂,—NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′,—SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂,—P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂; eachoccurrence of R^(5a) is independently an optionally substitutedC₁-C₆aliphatic group, halogen, —OR′, —SR′, —N(R′)₂, —NR′COR′,—NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂,—SOR′, —SO₂R′, —SO₂N(R′)₂, —NR'SO₂R′, —NR′SO₂N(R′)₂, —COCOR′,—COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂,or —OPO(R′)₂; and each occurrence of R is independently hydrogen or anoptionally substituted C₁₋₆ aliphatic group; and each occurrence of R′is independently hydrogen or an optionally substituted C₁₋₆ aliphaticgroup, a 3-8-membered saturated, partially unsaturated, or fullyunsaturated monocyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an 8-12 memberedsaturated, partially unsaturated, or fully unsaturated bicyclic ringsystem having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrencesof R′, are taken together with the atom(s) to which they are bound toform an optionally substituted 3-12 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur;provided that: a) when R³ is at the 7-position of the quinazoline ringthen: i) when R³ is Cl or Me, ring A is unsubstituted naphthyl, and R¹is hydrogen, then R² is not —(CH₂)₃NMe₂; ii) when R³ is Cl, the sum of qand y is 1 and the phenyl ring is substituted at the 4-position with Br,and R¹ is hydrogen, then R² is not Cy¹, wherein Cy¹ is bonded to thenitrogen atom through an optionally substituted C₁₋₄aliphatic group,wherein one or more methylene units in the C₁₋₄aliphatic group areoptionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—,—SO₂NR—, or —NRSO₂—; iii) when R³ is Cl or OMe, the sum of q and y is 1and the phenyl ring is substituted at the 4-position with either OMe orCl, and R¹ is hydrogen, then R² is not —CH(CH₃)(CH₂)₃N(Et)₂; iv) when R³is Me, OMe, or NO², and q and y are 0, then R¹ and R² are not bothmethyl; v) when R³ is OMe, q and y are 0, and R¹ is hydrogen, then R² isnot —SO₂(4-Me-phenyl); vi) when R³ is F, the sum of q and y is 1 and thephenyl ring is substituted at the 2-position with Cl, and R¹ ishydrogen, then R² is not —(CH₂)morpholino; and b) a) when R³ is at the6-position of the quinazoline ring then: i) when R³ is NH₂, Me, Cl, Br,—NHAc, the sum of q and y is 1 and the phenyl ring is substituted at the4-position with F, or ring A is naphthyl, and R¹ is hydrogen, then R² isnot —(CH₃)₃-4N(R′)₂; ii) when R³ is —OCH₂Ph, or OH, and q and y are 0,then when R¹ is hydrogen, R² is not Me, nBu, or —(CH₂)₂morpholino, or R¹and R² are not simultaneously Me or Et; iii) when R³ is Me or Cl, andthe sum of q and y are 1, then the phenyl ring is not substituted in the4-position with Br; iv) when R³ is Cl, q and y are 0, and R¹ ishydrogen, then R² is not —SO₂(4-Me-phenyl); v) when R³ is OMe, and q andy are 0, and R¹ is hydrogen, then R² is not —CH₂CH₂OH or—CH₂CH₂pyrrolidinyl; vi) when R³ is Cl or Br, the sum of q and y is 1,and the phenyl ring is substituted in the 4-position with —CH₂PO(OR′)₂,then R¹ is not hydrogen when R² is -Me, or R¹ and R² are notsimultaneously Me or Et; vii) when R³ is OH and q and y are 0, then R¹and R² are not simultaneously —CH₂CH₂OMe; viii) when R₃ is Cl, the sumof q and y is 1 and the phenyl ring is substituted in the 2-positionwith OnPr, and R¹ is hydrogen, then R² is not —CH₂(1,3-benzodioxol); ix)when R³ is OMe, OH, Br, C₁, NO₂, Me, and q and y are 0, then when R¹ ishydrogen, R² is not Me, —CH₂CH₂COOMe, —CH₂COOMe, or —(CH₂)₃CH₃, or R¹and R² are not simultaneously Me; and x) when R³ is Cl, the sum of q andy is 1 and the phenyl ring is substituted in the 4-position with Cl,then R¹ and R² are not simultaneously Me or iPr.
 103. The compound ofclaim 102, wherein a) one of R¹ or R² is hydrogen, and the other of R¹and R² is selected from: i) Cy¹ wherein Cy¹ is bonded directly to thenitrogen atom or is bonded through an optionally substitutedC₁₋₄aliphatic group, wherein one or more methylene units in theC₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—,—NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or ii) an optionally substitutedC₁₋₄aliphatic group, wherein one or more methylene units in theC₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—,—NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or b) R¹ and R² are eachindependently selected from Cy¹, wherein Cy¹ is bonded directly to thenitrogen atom or is bonded through an optionally substitutedC₁₋₄aliphatic group, wherein one or more methylene units in theC₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—,—NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or an optionally substitutedC₁₋₄aliphatic group, wherein one or more methylene units in theC₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO—,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—.
 104. The compound of claim102, wherein Cy¹ is:


105. The compound of claim 102, wherein R¹ is hydrogen or an optionallysubstituted C₁-C₄aliphatic group and R² is —CHR-Cy¹, wherein R ishydrogen or C₁-C₄alkyl, and Cy¹ is:


106. The compound of claim 102, wherein R¹ and R² groups are eachindependently an optionally substituted C₁₋₄aliphatic group and are eachindependently selected from optionally substituted methyl, ethyl,cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH₂CH₃, (CH₂)₂OCH₃,CH₂CO)OCH₂CH₃, CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, or n-butyl.
 107. The compoundof claim 102, wherein z is 0-5, and R⁴ groups, when present, are eachindependently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′,—SR′, —CH₂SR′₅—COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′,—SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected fromC₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic,arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆ alkyl, orheterocycloaliphaticC₁-C₆alkyl.
 108. The compound of claim 102, whereinz is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃,—CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂,—COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂,—SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂,—NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, oran optionally substituted group selected from -piperidinyl, piperizinyl,morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy,—CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl.
 109. Thecompound of claim 102, R³ is halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂,—OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂,COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted groupselected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic,heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl,cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.
 110. Thecompound of claim 104, wherein R³ is Cl, Br, F, CF₃, —OCF₃, Me, Et, CN,—COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃,—OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂,—CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substitutedgroup selected from -piperidinyl, piperizinyl, morpholino, phenyl,phenyloxy, benzyl, or benzyloxy.
 111. The compound of claim 102, whereinR³ is halogen, CN, optionally substituted C₁-C₆alkyl, OR′, N(R′)₂,CON(R′)₂, or NRCOR′.
 112. The compound of claim 102, wherein R³ is —Cl,—CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.
 113. The compound ofclaim 102, wherein R³ is at the 6-position of the quinazoline ring andis —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.
 114. The compound ofclaim 102, R³ is at the 7-position of the quinazoline ring and is —Cl,—CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.
 115. The compound ofclaim 102, wherein R³ is at the 6-position of the quinazoline ring andis —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.
 116. Thecompound of claim 102, wherein R³ is at the 7-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or—OCH₂CH₃.
 117. The compound of claim 102, wherein R³ is at the6-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′.
 118. Thecompound of claim 102, wherein R³ is at the 7-position of thequinazoline ring and is —CON(R′)₂, or NRCOR′.
 119. The compound of claim102, wherein y is 0-5, q is 0-2, and R⁵ and R^(5a) groups, when present,are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′,—CH₂OR′, —SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂, —S(O)₂N(R′)₂, —OCOR′, —COR′,—CO₂R′, —OCON(R′)₂, —NR′SO₂R′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′,—P(O)₂OR′, —PO(R′)₂, —OPO(R′)₂, or an optionally substituted groupselected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic,heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl,cycloaliphaticC₁-C₆ alkyl, or heterocycloaliphaticC₁-C₆alkyl.
 120. Thecompound of claim 102, wherein y is 0-5, and q is 1 or 2, and eachoccurrence of R^(5a) is independently Cl, Br, F, CF₃, Me, Et, CN, —COOH,—NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH,—OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃,—OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂,OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionallysubstituted benzyloxy.
 121. The compound of claim 102, wherein: y is 0,and R^(5a) is F; y is 0, q is 1, and R^(5a) is OR′; y is 0, q is 1 andR^(5a) is OH; y is 1, R^(5a) is OR′ and R⁵ is F, wherein OR′ issubstituted at the 2-position of the phenyl ring and F is substituted atthe 6-position of the phenyl ring; or y is 1, R^(5a) is OH and R⁵ is F,wherein OH is substituted at the 2-position of the phenyl ring and F issubstituted at the 6-position of the phenyl ring.
 122. The compound ofclaim 102, wherein R³ is substituted at the 6-position of thequinazoline ring, q is 1, and y is 0, and compounds have formula III:


123. The compound of claim 122, wherein: a) wherein R¹ and R² are eachindependently an optionally substituted group selected fromC₁₋₆aliphatic, Cy¹, wherein Cy¹ is a 5-7-membered monocyclic aryl ringor an 8-10-membered bicyclic aryl ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or is a3-12-membered saturated or partially unsaturated monocyclic ring having0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein Cy¹ is bonded directly to the nitrogen atom or is bonded throughan optionally substituted C₁₋₄aliphatic group, wherein one or moremethylene units in the C₁₋₄aliphatic group are optionally replaced with—NR—, —O—, —COO, —COO, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; wherein R¹and R², are each optionally and independently substituted at one or moresubstitutable carbon, nitrogen, or sulfur atoms with z independentoccurrences of —R⁴, wherein z is 0-5; b) z is 0-5 and R⁴ groups are eachindependently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂,—N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃,—SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃,—C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃,—COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionallysubstituted group selected from -piperidinyl, piperizinyl, morpholino,C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl,pyridyl, —CH₂pyridyl, or —CH₂thiazolyl; c) R³ is Cl, Br, F, CF₃, —OCF₃,Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃,—CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂,—SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionallysubstituted group selected from -piperidinyl, piperizinyl, morpholino,phenyl, phenyloxy, benzyl, or benzyloxy; and d) R^(5a) is Cl, F, CF₃,Me, Et, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —SO₂NH₂, —SO₂NHC(CH₃)₂,—OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl,OCOCH(CH₃)₂, OCO(cyclopentyl), or —COCH₃.
 124. The compound of claim122, wherein R³ is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃,—CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.
 125. Thecompound of claim 122, wherein R³ is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —OCH₃, or —OCH₂CH₃.
 126. The compound of claim 122, wherein R³ is—CON(R′)₂, or NRCOR′.
 127. The compound of claim 122, wherein R^(5a) isCl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃.
 128. The compound of claim122, wherein: R^(5a) is F; R^(5a) is OR′; or R^(5a) is OH.
 129. Thecompound of claim 122, wherein: a) Cy¹ is:

or R¹ and R² are each independently an optionally substitutedC₁₋₄aliphatic group and are each independently selected from optionallysubstituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl,(CO)OCH₂CH₃, (CH₂)₂OCH₃, CH₂CO)OCH₂CH₃, CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, orn-butyl; b) z is 0-5 and R⁴ groups are each independently Cl, Br, F,CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃,—CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃,—SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂,—C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃,—C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted groupselected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl,phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or—CH₂thiazolyl; c) R³ is Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂,—N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃,—OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl),—CONHCH₃, —CONHCH₂CH₃, or an optionally substituted group selected from-piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, orbenzyloxy; and d) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃,—CH₂OH, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃,—O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or—COCH₃.
 130. The compound of claim 122, wherein R³ is —Cl, —CH₃,—CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl),—OCH₃, —NH₂, —OCH₂CH₃, or —CN.
 131. The compound of claim 122, whereinR³ is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.
 132. Thecompound of claim 122, wherein R³ is —CON(R′)₂, or NRCOR′.
 133. Thecompound of claim 122, wherein R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃,—OCH₂CH₃.
 134. The compound of claim 122, wherein: R^(5a) is F; R^(5a)is OR′; or R^(5a) is OH.
 135. The compound of claim 102, wherein R³ issubstituted at the 7-position of the quinazoline ring, q is 1, and y is0, and compounds have formula IV:


136. The compound of claim 135, wherein: a) wherein R¹ and R² are eachindependently an optionally substituted group selected fromC₁₋₆aliphatic, Cy¹, wherein Cy¹ is a 5-7-membered monocyclic aryl ringor an 8-10-membered bicyclic aryl ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or is a3-12-membered saturated or partially unsaturated monocyclic ring having0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein Cy¹ is bonded directly to the nitrogen atom or is bonded throughan optionally substituted C₁₋₄aliphatic group, wherein one or moremethylene units in the C₁₋₄aliphatic group are optionally replaced with—NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; wherein R¹and R², are each optionally and independently substituted at one or moresubstitutable carbon, nitrogen, or sulfur atoms with z independentoccurrences of —R⁴, wherein z is 0-5; b) z is 0-5 and R⁴ groups are eachindependently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂,—N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃,—SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃,—C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃,—COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionallysubstituted group selected from -piperidinyl, piperizinyl, morpholino,C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl,pyridyl, —CH₂pyridyl, or —CH₂thiazolyl; c) R³ is Cl, Br, F, CF₃, —OCF₃,Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃,—CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂,—SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionallysubstituted group selected from -piperidinyl, piperizinyl, morpholino,phenyl, phenyloxy, benzyl, or benzyloxy; and d) R^(5a) is Cl, F, CF₃,Me, Et, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —SO₂NH₂, —SO₂NHC(CH₃)₂,—OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl,OCOCH(CH₃)₂, OCO(cyclopentyl), or —COCH₃.
 137. The compound of claim135, wherein R³ is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃,—CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.
 138. Thecompound of claim 135, wherein R³ is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —OCH₃, or —OCH₂CH₃.
 139. The compound of claim 135, wherein R³ is—CON(R′)₂, or NRCOR′.
 140. The compound of claim 135, wherein R^(5a) isCl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃.
 141. The compound of claim135, wherein: R^(5a) is F; R^(5a) is OR′; or R^(5a) is OH.
 142. Thecompound of claim 135, wherein: a) Cy¹ is:

or R¹ and R² are each independently an optionally substitutedC₁₋₄aliphatic group and are each independently selected from optionallysubstituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl,(CO)OCH₂CH₃, (CH₂)₂OCH₃, CH₂CO)OCH₂CH₃, CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, orn-butyl; b) z is 0-5 and R⁴ groups are each independently Cl, Br, F,CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃,—CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃,—SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂,—C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃,—C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted groupselected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl,phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or—CH₂thiazolyl; c) R³ is Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂,—N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃,—OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl),—CONHCH₃, —CONHCH₂CH₃, or an optionally substituted group selected from-piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, orbenzyloxy; and d) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃,—CH₂OH, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃,—O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or—COCH₃.
 143. The compound of claim 135, wherein R³ is —Cl, —CH₃,—CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl),—OCH₃, —NH₂, —OCH₂CH₃, or —CN.
 144. The compound of claim 135, whereinR³ is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.
 145. Thecompound of claim 135, wherein R³ is —CON(R′)₂, or NRCOR′.
 146. Thecompound of claim 135, wherein R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃,—OCH₂CH₃.
 147. The compound of claim 135, wherein: R^(5a) is F; R^(5a)is OR′; or R^(5a) is OH.
 148. A compound of formula V:

wherein R¹ and R² are each independently an optionally substituted groupselected from C₁₋₆aliphatic, Cy¹, wherein Cy¹ is a 5-7-memberedmonocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, oris a 3-12-membered saturated or partially unsaturated monocyclic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, wherein Cy¹ is bonded directly to the nitrogen atom or is bondedthrough an optionally substituted C₁₋₄aliphatic group, wherein one ormore methylene units in the C₁₋₄aliphatic group are optionally replacedwith —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or R¹and R², taken together with the nitrogen atom to which they are bound,form an optionally substituted 3-12-membered monocyclic or bicyclicsaturated or partially unsaturated ring having 0-3 additionalheteroatoms independently selected from nitrogen, sulfur, or oxygen;wherein R¹ and R², or the ring formed by R¹ and R² taken together, areeach optionally and independently substituted at one or moresubstitutable carbon, nitrogen, or sulfur atoms with z independentoccurrences of —R⁴, wherein z is 0-5; x is 0-4; y is 0-2; eachoccurrence of R³, R⁴, and R⁵ is independently Q-R^(X); wherein Q is abond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacentmethylene units of Q are optionally and independently replaced by —NR—,—S—, —O—, —CS—, —CO₂—, —COO, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—,—SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—,—SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of R^(X)is independently selected from —R′, ═O, ═NR′, halogen, —NO₂, —CN, —OR′,—SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′,—CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′,—NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂,—OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂; R^(5a) is an optionallysubstituted C₁-C₆aliphatic group, halogen, —OR′, —SR′, —N(R′)₂,—NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂,—OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂,—COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′,—PO(R′)₂, or —OPO(R′)₂; and each occurrence of R is independentlyhydrogen or an optionally substituted C₁₋₆ aliphatic group; and eachoccurrence of R′ is independently hydrogen or an optionally substitutedC₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated,or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-12membered saturated, partially unsaturated, or fully unsaturated bicyclicring system having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrencesof R′, are taken together with the atom(s) to which they are bound toform an optionally substituted 3-12 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur;provided that when x is 1 and R³ is 6-OMe, R¹ is hydrogen, and y and qare both 0, then R² is not —CH₂CH₂OCH₂CH₂OH or the monomethanesulfonatesalt.
 149. The compound of claim 148, wherein a) one of R¹ or R² ishydrogen, and the other of R¹ and R² is selected from: i) Cy¹ whereinCy¹ is bonded directly to the nitrogen atom or is bonded through anoptionally substituted C₁₋₄aliphatic group, wherein one or moremethylene units in the C₁₋₄aliphatic group are optionally replaced with—NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or ii) anoptionally substituted C₁₋₄aliphatic group, wherein one or moremethylene units in the C₁₋₄aliphatic group are optionally replaced with—NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or b) R¹and R² are each independently selected from Cy¹, wherein Cy¹ is bondeddirectly to the nitrogen atom or is bonded through an optionallysubstituted C₁₋₄aliphatic group, wherein one or more methylene units inthe C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or an optionally substitutedC₁₋₄aliphatic group, wherein one or more methylene units in theC₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO—,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—.
 150. The compound of claim148, wherein Cy¹ is:


151. The compound of claim 148, wherein R¹ is hydrogen or an optionallysubstituted C₁-C₄aliphatic group and R² is —CHR-Cy¹, wherein R ishydrogen or C₁-C₄alkyl, and Cy¹ is:


152. The compound of claim 148, wherein R¹ and R² groups are eachindependently an optionally substituted C₁₋₄aliphatic group and are eachindependently selected from optionally substituted methyl, ethyl,cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH₂CH₃, (CH₂)₂OCH₃,CH₂CO)OCH₂CH₃, CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, or n-butyl.
 153. The compoundof claim 148, wherein R¹ and R², taken together with the nitrogen atomto which they are bound, form an optionally substituted 3-12 memberedheterocyclyl ring having 1-3 heteroatoms independently selected fromnitrogen or oxygen and form a 3-12 membered heterocyclyl group selectedfrom:

wherein the ring formed by R¹ and R² taken together, is optionallysubstituted at one or more substitutable carbon, nitrogen, or sulfuratoms with z independent occurrences of —R⁴, and z is 0-5.
 154. Thecompound of claim 148, wherein R¹ and R² taken together is an optionallysubstituted ring selected from pyrrolidin-1-yl (ff), piperidin1-yl (dd),piperazin-1-yl (cc), or morpholin-4-yl (ee).
 155. The compound of claim148, wherein R¹ and R² taken together is an optionally substituted ringselected from pyrrolidin-1-yl (ff), piperidin1-yl (dd), orpiperazin-1-yl (cc).
 156. The compound of claim 148, wherein z is 0-5,and R⁴ groups, when present, are each independently halogen, CN, NO₂,—N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′,—CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or anoptionally substituted group selected from C₁₋C₆aliphatic, aryl,heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆ alkyl, orheterocycloaliphaticC₁-C₆alkyl.
 157. The compound of claim 148, whereinz is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃,—CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂,—COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂,—SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂,—NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, oran optionally substituted group selected from -piperidinyl, piperizinyl,morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy,—CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl.
 158. Thecompound of claim 148, wherein x is 0-4, and R³ groups, when present,are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′,—CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′,—NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted groupselected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic,heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl,cycloaliphaticC₁-C₆ alkyl, or heterocycloaliphaticC₁-C₆alkyl.
 159. Thecompound of claim 148, wherein R¹ and R², taken together is selectedfrom: a. optionally substituted azetidin-1-yl (jj), wherein z is 1 or 2and at least one occurrence of R⁴ is —NRSO₂R′, —NRCOOR′, or —NRCOR′; b.optionally substituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is—NRSO₂R′; c. optionally substituted azetidin-1-yl (jj), wherein z is 1and R⁴ is —NRCOOR′; d. optionally substituted azetidin-1-yl (jj),wherein z is 1 and R⁴ is —NRCOR′; e. optionally substitutedpyrrolidin-1-yl (ff), wherein z is 1 or 2 and R⁴ is Cl, Br, F, CF₃, CH₃,—CH₂CH₃, —OR′, or —CH₂OR′; f. optionally substituted piperidin-1-yl(dd), wherein z is 1 or 2 and at least one occurrence of R⁴ is Cl, Br,F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′, —NRSO₂R′, —NRCOOR′, or—OCON(R′)₂; g. optionally substituted piperidin-1-yl (dd), wherein z is1 and R⁴ is F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′; h. optionallysubstituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is —NRSO₂R′; i.optionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is—NRCOOR′; j. optionally substituted piperazin-1-yl (cc), wherein z is 1or 2 and at least one occurrence of R⁴ is —SOR′, —CON(R′)₂, —SO₂N(R′)₂,—COR′, or —COOR′; k. optionally substituted piperazin-1-yl (cc), whereinz is 1 and R⁴ is —SOR′ l. optionally substituted piperazin-1-yl (cc),wherein z is 1 and R⁴ is —COOR′; m. optionally substitutedpiperazin-1-yl (cc), wherein z is 1 and R⁴ is —CON(R′)₂; n. optionallysubstituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —SO₂N(R′)₂; oro. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is—COR′.
 160. The compound of claim 148, wherein x is 1 or 2, and eachoccurrence of R³ is independently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN,—COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃,—OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂,—CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substitutedgroup selected from -piperidinyl, piperizinyl, morpholino, phenyl,phenyloxy, benzyl, or benzyloxy.
 161. The compound of claim 148, whereinx is 1 or 2 and each R³ group is independently halogen, CN, optionallysubstituted C₁-C₆alkyl, OR′, N(R′)₂, CON(R′)₂, or NRCOR′.
 162. Thecompound of claim 148, wherein x is 1 or 2, and each R³ group is —Cl,—CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.
 163. The compound ofclaim 148, wherein x is 1 and R³ is at the 6-position of the quinazolinering and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.
 164. The compound ofclaim 148, wherein x is 1 and R³ is at the 7-position of the quinazolinering and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.
 165. The compound ofclaim 148, wherein x is 1 and R³ is at the 6-position of the quinazolinering and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.166. The compound of claim 148, wherein x is 1 and R³ is at the7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —OCH₃, or —OCH₂CH₃.
 167. The compound of claim 148, wherein x is1 and R³ is at the 6-position of the quinazoline ring and is —CON(R′)₂,or NRCOR′.
 168. The compound of claim 148, wherein x is 1 and R³ is atthe 7-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′. 169.The compound of claim 148, wherein y is 0-2, q is 0-2, and R⁵ and R^(5a)groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂,—CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂,—S(O)₂N(R′)₂, —OCOR′, —COR′, —CO₂R′, —OCON(R′)₂, —NR′SO₂R′,—OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, —OPO(R′)₂,or an optionally substituted group selected from C₁₋C₆aliphatic, aryl,heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.
 170. The compound of claim 148, whereiny is 0-2, and q is 1 or 2, and each occurrence of R^(5a) isindependently Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂,—N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃,—CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃,—O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl),—COCH₃, optionally substituted phenoxy, or optionally substitutedbenzyloxy.
 171. The compound of claim 148, wherein: a) y is 0, and q is1 and R^(5a) is F; b) y is 0, q is 1, and R^(5a) is OR′; c) y is 0, q is1 and R^(5a) is OH; d) y is 0, q is 2 and one occurrence of R^(5a) isOR′ and the other occurrence of R^(5a) is F; or e) y is 0, q is 2 andone occurrence of R^(5a) is OH and the other occurrence of R^(5a) is F.172. The compound of claim 148, wherein: a) R¹ and R² taken together isan optionally substituted ring selected from azetidin-1-yl (jj),pyrrolidin-1-yl (ff), piperidin1-yl (dd), or piperazin-1-yl (cc); one ofR¹ or R² is hydrogen, and the other of R¹ and R² is selected from Cy¹,wherein Cy¹ is bonded directly to the nitrogen atom or is bonded throughan optionally substituted C₁₋₄aliphatic group, wherein one or moremethylene units in the C₁₋₄aliphatic group are optionally replaced with—NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—, or anoptionally substituted C₁₋₄aliphatic group, wherein one or moremethylene units in the C₁₋₄aliphatic group are optionally replaced with—NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or R¹ andR² are each independently selected from an optionally substitutedC₁₋₄aliphatic group, wherein one or more methylene units in theC₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—,—NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or Cy¹ wherein Cy¹ is bonded to thenitrogen atom directly or is bonded through an optionally substitutedC₁₋₄aliphatic group, wherein one or more methylene units in theC₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—,—NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; b) z is 0-5 and R⁴ groups are eachindependently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂,—N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃,—SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃,—C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃,—COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionallysubstituted group selected from -piperidinyl, piperizinyl, morpholino,C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl,pyridyl, —CH₂pyridyl, or —CH₂thiazolyl; c) x is 0, 1, or 2, and eachoccurrence of R³ is independently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN,—COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃,—OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂,—CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substitutedgroup selected from -piperidinyl, piperizinyl, morpholino, phenyl,phenyloxy, benzyl, or benzyloxy; d) wherein y is 0-2, and R⁵ groups,when present, are each independently Cl, Br, F, CF₃, Me, Et, CN, —COOH,—NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH,—OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃,—OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂,OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionallysubstituted benzyloxy; and e) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃,—OCH₂CH₃, —CH₂OH, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃,—O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or—COCH₃.
 173. The compound of claim 172, wherein x is 1 and R³ is at the6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃,or —CN.
 174. The compound of claim 172 wherein x is 1 and R³ is at the7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃,or —CN.
 175. The compound of claim 172, wherein x is 1 and R³ is at the6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —OCH₃, or —OCH₂CH₃.
 176. The compound of claim 172, wherein x is1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃,—CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.
 177. The compound of claim172, wherein x is 1 and R³ is at the 6-position of the quinazoline ringand is —CON(R′)₂, or NRCOR′.
 178. The compound of claim 172, wherein xis 1 and R³ is at the 7-position of the quinazoline ring and is—CON(R′)₂, or NRCOR′.
 179. The compound of claim 172, wherein R^(5a) isCl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃.
 180. The compound of claim172, wherein: a) y is 0, and q is 1 and R^(5a) is F; b) y is 0, q is 1,and R^(5a) is OR′; c) y is 0, q is 1 and R^(5a) is OH; d) y is 0, q is 2and one occurrence of R^(5a) is OR′ and the other occurrence of R^(5a)is F; or e) y is 0, q is 2 and one occurrence of R^(5a) is OH and theother occurrence of R^(5a) is F.
 181. The compound of claim 172,wherein: a) Cy¹ is:

or R¹ and R² are each independently an optionally substitutedC₁₋₄aliphatic group and are each independently selected from optionallysubstituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl,(CO)OCH₂CH₃, (CH₂)₂OCH₃, CH₂CO)OCH₂CH₃, CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, orn-butyl; b) z is 0-5 and R⁴ groups are each independently Cl, Br, F,CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃,—CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃,—SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂,—C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃,—C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted groupselected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl,phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or—CH₂thiazolyl; c) x is 0, 1, or 2, and each occurrence of R³ isindependently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂,—N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃,—CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃,—CONHCH₂CH₃, or an optionally substituted group selected from-piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, orbenzyloxy; d) wherein y is 0-5, and R⁵ groups, when present, are eachindependently Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂,—N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃,—CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃,—O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl),—COCH₃, optionally substituted phenoxy, or optionally substitutedbenzyloxy; and e) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃,—CH₂OH, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃,—O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or—COCH₃.
 182. The compound of claim 172, wherein x is 1 and R³ is at the6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃,or —CN.
 183. The compound of claim 172 wherein x is 1 and R³ is at the7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃,or —CN.
 184. The compound of claim 172, wherein x is 1 and R³ is at the6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —OCH₃, or —OCH₂CH₃.
 185. The compound of claim 172, wherein x is1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃,—CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.
 186. The compound of claim172, wherein x is 1 and R³ is at the 6-position of the quinazoline ringand is —CON(R′)₂, or NRCOR′.
 187. The compound of claim 172, wherein xis 1 and R³ is at the 7-position of the quinazoline ring and is—CON(R′)₂, or NRCOR′.
 188. The compound of claim 172, wherein R^(5a) isCl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃.
 189. The compound of claim172, wherein R^(5a) is OR′.
 190. The compound of claim 172, whereinR^(5a) is OH.
 191. The compound of claim 172, wherein R^(5a) is F. 192.A compound of formula I-B-i:

or a pharmaceutically acceptable salt thereof, wherein R¹ is selectedfrom C₁₋₆aliphatic, Cy¹, wherein Cy¹ is a 5-7-membered monocyclic arylring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or is a3-12-membered saturated or partially unsaturated monocyclic ring having0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein Cy¹ is bonded directly to the nitrogen atom or is bonded throughan optionally substituted C₁₋₄aliphatic group, wherein one or moremethylene units in the C₁₋₄aliphatic group are optionally replaced with—NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; wherein R¹is optionally substituted at one or more substitutable carbon, nitrogen,or sulfur atoms with z independent occurrences of —R⁴, wherein z is 0-5;x is 0-4; y is 0-4; each occurrence of R³, R⁴, and R⁵ is independentlyQ-R^(X); wherein Q is a bond or is a C₁-C₆ alkylidene chain wherein upto two non-adjacent methylene units of Q are optionally andindependently replaced by —NR—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—,—COCO—, —CONR—, —NRCO—, —NRCO₂—, —SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—,—OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or—POR—; and each occurrence of R^(X) is independently selected from —R′,═O, ═NR′, halogen, —NO₂, —CN, —OR′, —SR′, —N(R′)₂, —NR′COR′,—NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂,—SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′,—COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂,or —OPO(R′)₂; each occurrence of R^(5a) is independently an optionallysubstituted C₁-C₆aliphatic group, halogen, —OR′, —SR′, —N(R′)₂,—NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂,—OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂,—COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′,—PO(R′)₂, or —OPO(R′)₂; and each occurrence of R is independentlyhydrogen or an optionally substituted C₁₋₆ aliphatic group; and eachoccurrence of R′ is independently hydrogen or an optionally substitutedC₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated,or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-12membered saturated, partially unsaturated, or fully unsaturated bicyclicring system having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrencesof R′, are taken together with the atom(s) to which they are bound toform an optionally substituted 3-12 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur;provided that: a) when R^(5a) is Me, Cl, or OMe, and x is 0, then R¹ isnot Et or Me; b) when R^(5a) is Cl, x is 3, and the three occurrences ofR³ are 6-Me, 7-COOEt, and 8-Me, then R¹ is not —(CH₂)₂piperidin-1-yl; c)when R^(5a) is Me, x is 1 and R³ is NO₂ or NH₂, then R¹ is not Et; d)when R^(5a) is OH, NHMe, or N(NO)Me, and x is 0, then R¹ is not Et, Meor —CH₂CH═CH₂; e) when R^(5a) is NH², and x is 0, then R¹ is not —COCH₃;f) when R^(5a) is Cl or Me, and y is 0 or 1 and when y is 1, R⁵ is 4-Cl,and x is 0, then R¹ is not 4-CN-phenyl, 4-Me-phenyl, 4-OMe-phenyl,4-Cl-phenyl, 4-NO₂-phenyl, —CH₂CH₂NHMe, Et, Me, 4-COOMe-phenyl, —CH₂Ph,iPr, 2-Me-phenyl, 4-phenyl-phenyl, or —CH₂CH═CH₂.
 193. The compound ofclaim 192, wherein a) R¹ is selected from: i) Cy¹ wherein Cy¹ is bondeddirectly to the nitrogen atom or is bonded through an optionallysubstituted C₁₋₄aliphatic group, wherein one or more methylene units inthe C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or ii) an optionallysubstituted C₁₋₄aliphatic group, wherein one or more methylene units inthe C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—.
 194. The compound of claim192 wherein Cy¹ is:


195. The compound of claim 192, wherein R¹ is —CHR-Cy¹, wherein R ishydrogen or C₁-C₄alkyl and Cy¹ is:


196. The compound of claim 192, wherein R¹ is an optionally substitutedC₁₋₄aliphatic group and are each independently selected from optionallysubstituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl,(CO)OCH₂CH₃, (CH₂)₂OCH₃, CH₂CO)OCH₂CH₃, CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, orn-butyl.
 197. The compound of claim 192, wherein z is 0-5, and R⁴groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂,—CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′₅—COOR′, —NRCOR′, —CON(R′)₂,—OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionallysubstituted group selected from C₁₋C₆aliphatic, aryl, heteroaryl,cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆ alkyl, orheterocycloaliphaticC₁-C₆alkyl.
 198. The compound of claim 192, whereinz is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃,—CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂,—COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂,—SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂,—NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, oran optionally substituted group selected from -piperidinyl, piperizinyl,morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy,—CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl.
 199. Thecompound of claim 192, R³ is halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂,—OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂,COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted groupselected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic,heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl,cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.
 200. Thecompound of claim 192, wherein R³ is Cl, Br, F, CF₃, —OCF₃, Me, Et, CN,—COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃,—OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂,—CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substitutedgroup selected from -piperidinyl, piperizinyl, morpholino, phenyl,phenyloxy, benzyl, or benzyloxy.
 201. The compound of claim 192, whereinR³ is halogen, CN, optionally substituted C₁-C₆alkyl, OR′, N(R′)₂,CON(R′)₂, or NRCOR′.
 202. The compound of claim 192, wherein R³ is —Cl,—CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.
 203. The compound ofclaim 192, wherein R³ is at the 6-position of the quinazoline ring andis —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.
 204. The compound ofclaim 192, R³ is at the 7-position of the quinazoline ring and is —Cl,—CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃,—CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.
 205. The compound ofclaim 192, wherein R³ is at the 6-position of the quinazoline ring andis —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.
 206. Thecompound of claim 192, wherein R³ is at the 7-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or—OCH₂CH₃.
 207. The compound of claim 192, wherein R³ is at the6-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′.
 208. Thecompound of claim 192, wherein R³ is at the 7-position of thequinazoline ring and is —CON(R′)₂, or NRCOR′.
 209. The compound of claim192, wherein y is 0-5, q is 0-2, and R⁵ and R^(5a) groups, when present,are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′,—CH₂OR′, —SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂, —S(O)₂N(R′)₂, —OCOR′, —COR′,—CO₂R′, —OCON(R′)₂, —NR′SO₂R′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′,—P(O)₂OR′, —PO(R′)₂, —OPO(R′)₂, or an optionally substituted groupselected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic,heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl,cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.
 210. Thecompound of claim 192, wherein y is 0-5, and q is 1 or 2, and eachoccurrence of R^(5a) is independently Cl, Br, F, CF₃, Me, Et, CN, —COOH,—NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH,—OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃,—OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂,OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionallysubstituted benzyloxy.
 211. The compound of claim 192, wherein: a) y is0, q is 1 and R^(5a) is F; b) y is 0, q is 1, and R^(5a) is OR′; c) y is0, q is 1 and R^(5a) is OH; d) y is 1, R^(5a) is OR′ and R⁵ is F,wherein OR′ is substituted at the 2-position of the phenyl ring and F issubstituted at the 6-position of the phenyl ring; or e) y is 1, R^(5a)is OH and R⁵ is F, wherein OH is substituted at the 2-position of thephenyl ring and F is substituted at the 6-position of the phenyl ring.211. A composition comprising a compound of any one of claims 1-211; anda pharmaceutically acceptable carrier, vehicle, or diluent.
 212. Amethod of treating or lessening the severity of a disease, disorder, orcondition selected from acute, chronic, neuropathic, or inflammatorypain, arthritis, migrane, cluster headaches, trigeminal neuralgia,herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions,neurodegenerative disorders, psychiatric disorders such as anxiety anddepression, myotonia, arrythmia, movement disorders, neuroendocrinedisorders, ataxia, multiple sclerosis, irritable bowel syndrome,incontinence, visceral pain, osteoarthritis pain, postherpeticneuralgia, diabetic neuropathy, radicular pain, sciatica, back pain,head or neck pain, severe or intractable pain, nociceptive pain,breakthrough pain, postsurgical pain, or cancer pain comprising the stepof administering to said patient an effective amount of a compound offormula I:

or a pharmaceutically acceptable salt thereof, wherein: X is O or NR²;wherein R¹ and R² are each independently an optionally substituted groupselected from hydrogen, C₁₋₆aliphatic, or Cy¹, wherein Cy¹ is a5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or is a 3-12-membered saturated, or partially unsaturatedmonocyclic or bicyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein Cy¹ is bondeddirectly to the nitrogen atom or is bonded through an optionallysubstituted C₁₋₄aliphatic group, wherein one or more methylene units inthe C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or R¹ and R², taken togetherwith the nitrogen atom to which they are bound, form an optionallysubstituted 3-12-membered monocyclic or bicyclic saturated, partiallyunsaturated, or fully unsaturated ring having 0-3 additional heteroatomsindependently selected from nitrogen, sulfur, or oxygen; wherein R¹ andR², or the ring formed by R¹ and R² taken together, are each optionallyand independently substituted at one or more substitutable carbon,nitrogen, or sulfur atoms with z independent occurrences of —R⁴, whereinz is 0-5; Ring A is a 5-7-membered monocyclic aryl ring or an8-10-membered bicyclic aryl ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or is a 3-12-memberedmonocyclic or bicyclic saturated or partially unsaturated monocyclicring having 0-3 heteroatoms independently selected from nitrogen,oxygen, or sulfur, wherein ring A is optionally substituted with yindependent occurrences of —R⁵, wherein y is 0-5, and is additionallyoptionally substituted with q independent occurrences of R^(5a), whereinq is 0-2; x is 0-4; each occurrence of R³, R⁴, and R⁵ is independentlyQ-R^(X); wherein Q is a bond or is a C₁-C₆ alkylidene chain wherein upto two non-adjacent methylene units of Q are optionally andindependently replaced by —NR—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—,—COCO—, —CONR—, —NRCO—, —NRCO₂—, —SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—,—OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or—POR—; and each occurrence of R^(X) is independently selected from —R′,═O, ═NR′, halogen, —NO₂, —CN, —OR′, —SR′, —N(R′)₂, —NR′COR′,—NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂,—SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′,—COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂,or —OPO(R′)₂; each occurrence of R^(5a) is independently an optionallysubstituted C₁-C₆aliphatic group, halogen, —OR′, —SR′, —N(R′)₂,—NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂,—OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂,—COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′,—PO(R′)₂, or —OPO(R′)₂; and each occurrence of R is independentlyhydrogen or an optionally substituted C₁₋₆ aliphatic group; and eachoccurrence of R′ is independently hydrogen or an optionally substitutedC₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated,or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-12membered saturated, partially unsaturated, or fully unsaturated bicyclicring system having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrencesof R′, are taken together with the atom(s) to which they are bound toform an optionally substituted 3-12 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfurprovided that: i) when x is 1 and R³ is optionally substituted 6-phenylor 6-pyridyl, and R¹ is hydrogen, then R² is not Cy¹; and ii)piperazine,1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4(2-furanylcarbonyl)-monohydrochlorideandpiperazine,1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4[(2,3-dihydro-1,4-benzodioxin-2-yl)carbonyl]-are excluded.
 213. The method of claim 212, wherein the disease,condition, or disorder is implicated in the activation or hyperactivityof voltage-gated sodium channels.
 214. The method of claim 212, whereinthe disease, condition, or disorder is implicated in the activation orhyperactivity of calcium channels.
 215. The method of claim 212, whereinthe disease, condition, or disorder is acute, chronic, neuropathic, orinflammatory pain.
 216. The method of claim 212, wherein the disease,condition, or disorder is radicular pain, sciatica, back pain, headpain, or neck pain.
 217. The method of claim 212, wherein the disease,condition, or disorder is severe or intractable pain, acute pain,postsurgical pain, back pain, or cancer pain.
 218. A method ofinhibiting one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5,NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 activity in: (a) a patient; or(b) a biological sample; which method comprises administering to saidpatient, or contacting said biological sample with a compound of formulaI:

or a pharmaceutically acceptable salt thereof, wherein: X is O or NR²;wherein R¹ and R² are each independently an optionally substituted groupselected from hydrogen, C₁₋₆aliphatic, or Cy¹, wherein Cy¹ is a5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or is a 3-12-membered saturated, or partially unsaturatedmonocyclic or bicyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein Cy¹ is bondeddirectly to the nitrogen atom or is bonded through an optionallysubstituted C₁₋₄aliphatic group, wherein one or more methylene units inthe C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or R¹ and R², taken togetherwith the nitrogen atom to which they are bound, form an optionallysubstituted 3-12-membered monocyclic or bicyclic saturated, partiallyunsaturated, or fully unsaturated ring having 0-3 additional heteroatomsindependently selected from nitrogen, sulfur, or oxygen; wherein R¹ andR², or the ring formed by R¹ and R² taken together, are each optionallyand independently substituted at one or more substitutable carbon,nitrogen, or sulfur atoms with z independent occurrences of —R⁴, whereinz is 0-5; Ring A is a 5-7-membered monocyclic aryl ring or an8-10-membered bicyclic aryl ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or is a 3-12-memberedmonocyclic or bicyclic saturated or partially unsaturated monocyclicring having 0-3 heteroatoms independently selected from nitrogen,oxygen, or sulfur, wherein ring A is optionally substituted with yindependent occurrences of —R⁵, wherein y is 0-5, and is additionallyoptionally substituted with q independent occurrences of R^(5a), whereinq is 0-2; x is 0-4; each occurrence of R³, R⁴, and R⁵ is independentlyQ-R^(X); wherein Q is a bond or is a C₁-C₆ alkylidene chain wherein upto two non-adjacent methylene units of Q are optionally andindependently replaced by —NR—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—,—COCO—, —CONR—, —NRCO—, —NRCO₂—, —SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—,—OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or—POR—; and each occurrence of R^(X) is independently selected from —R′,═O, ═NR′ halogen, —NO₂, —CN, —OR′, —SR′, —N(R′)₂, —NR′COR′,—NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂,—SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′,—COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂,or —OPO(R′)₂; each occurrence of R^(5a) is independently an optionallysubstituted C₁-C₆aliphatic group, halogen, —OR′, —SR′, —N(R′)₂,—NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂,—OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂,—COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′,—PO(R′)₂, or —OPO(R′)₂; and each occurrence of R is independentlyhydrogen or an optionally substituted C₁₋₆ aliphatic group; and eachoccurrence of R′ is independently hydrogen or an optionally substitutedC₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated,or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-12membered saturated, partially unsaturated, or fully unsaturated bicyclicring system having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrencesof R′, are taken together with the atom(s) to which they are bound toform an optionally substituted 3-12 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.219. The method of claim 212 or 218, wherein X is NR², and compoundshave the structure of formula I-A:


220. The method of claim 212 or 218, wherein X is O, and compounds havethe structure of formula I-B:


221. The method of claim 212 or 218, wherein a) one of R¹ or R² ishydrogen, and the other of R¹ and R² is selected from: i) an optionallysubstituted C₁₋₄aliphatic group, wherein one or more methylene units inthe C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or Cy¹, wherein Cy¹ is a5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or is a 3-12-membered saturated, or partially unsaturatedmonocyclic or bicyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein Cy¹ is bondeddirectly to the nitrogen atom or is bonded through an optionallysubstituted C₁₋₄aliphatic group, wherein one or more methylene units inthe C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or ii) an optionallysubstituted C₁₋₄aliphatic group, wherein one or more methylene units inthe C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or b) R¹ and R² are eachindependently selected from Cy¹, wherein Cy¹ is a 5-7-memberedmonocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, oris a 3-12-membered saturated, or partially unsaturated monocyclic orbicyclic ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, wherein Cy¹ is bonded directly to thenitrogen atom or is bonded through an optionally substitutedC₁₋₄aliphatic group, wherein one or more methylene units in theC₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—,—NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or from an optionally substitutedC₁₋₄aliphatic group, wherein one or more methylene units in theC₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO—,—OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—.
 222. The method of claim 212or 218, wherein Cy¹ is:


223. The method of claim 212 or 218, wherein R¹ is hydrogen or anoptionally substituted C₁-C₄aliphatic group and R² is —CH₂-Cy¹, whereinCy¹ is:


224. The method of claim 212 or 218, wherein R¹ and R² groups are eachindependently an optionally substituted C₁₋₄aliphatic group and are eachindependently selected from optionally substituted methyl, ethyl,cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH₂CH₃, (CH₂)₂OCH₃,CH₂CO)OCH₂CH₃, CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, or n-butyl.
 225. The methodof claim 212 or 218, wherein R¹ and R², taken together with the nitrogenatom to which they are bound, form an optionally substituted 3-12membered heterocyclyl ring having 1-3 heteroatoms independently selectedfrom nitrogen or oxygen and form a 3-12 membered heterocyclyl groupselected from:

wherein the ring formed by R¹ and R² taken together, is optionallysubstituted at one or more substitutable carbon, nitrogen, or sulfuratoms with z independent occurrences of —R⁴, and z is 0-5.
 226. Themethod of claim 212 or 218, wherein R¹ and R² taken together is anoptionally substituted ring selected from azetidin-1-yl (jj),pyrrolidin-1-yl (ff), piperidin1-yl (dd), piperazin-1-yl (cc), ormorpholin-4-yl (ee).
 227. The method of claim 212 or 218, wherein R¹ andR² taken together is an optionally substituted ring selected fromazetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidin1-yl (dd), orpiperazin-1-yl (cc).
 228. The method of claim 212 or 218, wherein z is0-5, and R⁴ groups, when present, are each independently halogen, CN,NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′,—CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or anoptionally substituted group selected from C₁₋C₆aliphatic, aryl,heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.
 229. The method of claim 212 or 218,wherein z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃,CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃,—CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃,—SO₂CH(CH₃)₂₅—SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂,—C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃,—C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted groupselected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl,phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or—CH₂thiazolyl.
 230. The method of claim 212 or 218, wherein R¹ and R²,taken together is selected from: a. optionally substituted azetidin-1-yl(jj), wherein z is 1 or 2 and at least one occurrence of R⁴ is —NRSO₂R′,—NRCOOR′, or —NRCOR′; b. optionally substituted azetidin-1-yl (jj),wherein z is 1 and R⁴ is —NRSO₂R′; c. optionally substitutedazetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRCOOR′; d. optionallysubstituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRCOR′; e.optionally substituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R⁴is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′; f. optionallysubstituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least oneoccurrence of R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′,—NRSO₂R′, —NRCOOR′, or —OCON(R′)₂; g. optionally substitutedpiperidin-1-yl (dd), wherein z is 1 and R⁴ is F, CF₃, CH₃, —CH₂CH₃,—OR′, or —CH₂OR′; h. optionally substituted piperidin-1-yl (dd), whereinz is 1 and R⁴ is —NRSO₂R′; i. optionally substituted piperidin-1-yl(dd), wherein z is 1 and R⁴ is —NRCOOR′; j. optionally substitutedpiperazin-1-yl (cc), wherein z is 1 or 2 and at least one occurrence ofR⁴ is —SOR′, —CON(R′)₂, —SO₂N(R′)₂, —COR′, or —COOR′; k. optionallysubstituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —SOR′ l.optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is—COOR′; m. optionally substituted piperazin-1-yl (cc), wherein z is 1and R⁴ is —CON(R′)₂; n. optionally substituted piperazin-1-yl (cc),wherein z is 1 and R⁴ is —SO₂N(R′)₂; or o. optionally substitutedpiperazin-1-yl (cc), wherein z is 1 and R⁴ is —COR′.
 231. The method ofclaim 212 or 218, wherein x is 0-4, and R³ groups, when present, areeach independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′,—SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′,—SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected fromC₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic,arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.
 232. The method of claim 212 or 218,wherein x is 1 or 2, and each occurrence of R³ is independently Cl, Br,F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂,—O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃,—NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or anoptionally substituted group selected from -piperidinyl, piperizinyl,morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.
 233. The method ofclaim 212 or 218, wherein x is 1 or 2 and each R³ group is independentlyhalogen, CN, optionally substituted C₁-C₆alkyl, OR′, N(R′)₂, CON(R′)₂,or NRCOR′.
 234. The method of claim 212 or 218, wherein x is 1 or 2, andeach R³ group is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃,—CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.
 235. Themethod of claim 212 or 218, wherein x is 1 and R³ is at the 6-positionof the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃,—CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or—CN.
 236. The method of claim 212 or 218, wherein x is 1 and R³ is atthe 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F,—CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂,—OCH₂CH₃, or —CN.
 237. The method of claim 212 or 218, wherein x is 1and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃,—CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.
 238. The method of claim212 or 218, wherein x is 1 and R³ is at the 7-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or—OCH₂CH₃.
 239. The method of claim 212 or 218, wherein x is 1 and R³ isat the 6-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′.240. The method of claim 212 or 218, wherein x is 1 and R³ is at the7-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′.
 241. Themethod of claim 212 or 218, wherein y is 0-5, q is 0-2, and R⁵ andR^(5a) groups, when present, are each independently halogen, CN, NO₂,—N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂,—S(O)₂N(R′)₂, —OCOR′, —COR′, —CO₂R′, —OCON(R′)₂, —NR′SO₂R′,—OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, —OPO(R′)₂,or an optionally substituted group selected from C₁₋C₆aliphatic, aryl,heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.
 242. The method of claim 212 or 218,wherein q is 1 and y is 0 or 1, and R^(5a) is F, OR′, or OH.
 243. Themethod of claim 212 or 218, wherein ring A is selected from:


244. The method of claim 212 or 218, wherein ring A is selected fromoptionally substituted phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, orpyrrol-1-yl.
 245. The method of claim 212 or 218, comprisingadministering a compound of any one of claims 1-211.
 246. The method ofclaim 218 or 245, comprising inhibiting NaV1.3 or NaV1.8 activity. 247.The method of claim 218 or 245, comprising inhibiting CaV2.2 activity.248. The method of claim 218 or 245, comprising inhibiting NaV1.8 andCaV2.2 activity.
 249. The method of claim 218 or 245, comprisinginhibiting NaV1.8 activity.